Files reveal approved school drug trial plans in 1960s

File from National Archives

Home Office doctors gave the go-ahead for experimental drug trials on children at two approved schools in the 1960s, National Archives files show.

Parents were not consulted and the issue of consent was left to managers.

At Richmond Hill Approved School in North Yorkshire, housing pupils aged 15 and older, the most disruptive boys were given an anticonvulsant drug to see if it would control behaviour.

The trial of a sedative on girls at a school near Leeds did not proceed.

The proposal had been to give all girls at Springhead Park Approved School in Rothwell, which cared for 14 and 15 year olds, Haloperidol, a powerful sedative now used largely as an anti-psychotic.

‘Restless and aggressive’

Approved Schools were on a level between between a children’s home and Borstal.

While children were usually sent there by juvenile courts, they were not imprisoned; the sites were funded and inspected by the Home Office and run by voluntary organisations.

The National Archives files feature discussions about the plans for the drug trials from three doctors who are all now deceased.

In a document dating from late 1967, Dr JR Hawkings, a psychiatrist attached to Richmond Hill, wrote to the Home Office asking permission to conduct a drug trial on boys who were “impulsive, explosive, irritable, restless and aggressive”.

The outside of the former Richmond Hill Approved School in 2016
One of the buildings which formerly housed the Richmond Hill approved school

He wanted to give some of them a drug called Beclamide. The anticonvulsant, which has sedative effects and was prescribed for epilepsy, is no longer widely in use.

Although Dr Hawkings said this would be ” a perfectly normal and legitimate therapy for certain types of disturbed adolescent”, he also said that it had not been widely tested on such boys.

It was to be a “double blind” trial, with a control group given a placebo, and another group given the drug.

But there is no indication that the trial was discussed or explained to participants or suggestion that their consent was sought.

‘Maximum support’

The papers show the Home Office psychiatrist Dr Pamela Mason welcomed Dr Hawkings’s plan.

On 1 November 1967 she wrote: “From the clinical or practical point of view these are the boys that can produce considerable problems within a school and this sort of research into possible drug treatment is to be welcomed…

“I would recommend maximum support for this project.”

According to notes on the file, the trial went ahead in 1968, with boys given the drug for six months.

There is no record of the outcome in the documents, nor could I find any published paper in medical journals

And the files show the school headmaster told the Home Office that “in view of assurances from the school doctor, from Dr Hawkings… and from the doctor acting for the manufacturers, the managers had decided that there was no need to consult the parents”.

‘In strict confidence’

Bob Hammal, a teacher at Richmond Hill between 1968 and 1972, was appalled to learn of the trial.

He remembered there were challenges – but generally recalls a good relationship between staff and the boys.

Bob Hammal
Former teacher Bob Hammal says he was shocked by the revelations

“What really did shock me more than anything was that parental consent was not sought and was not thought to be necessary by the powers-that-be,” he said.

He believes that had he, or other colleagues, known at the time, they would have tried to stop it, or acted as a whistleblower if that was not possible.

As the Richmond Hill trial got under way, a second trial was proposed, again by a school psychiatrist, at Springhead Park Approved School for girls in Rothwell near Leeds.

This was a sister school to the better known Duncroft in Surrey, a small institution for girls of higher intelligence.

In November 1968, Dr Joyce Galbraith wrote to Dr Mason at the Home Office “in strict confidence”.

She said she was increasingly concerned about the tone of the school and unrest amongst the staff.

To calm the situation, she suggested giving Haloperidol to every girl in the school, for 18 weeks.

She wrote: “My suggestion is that we should try some form of drug trial to see if, by allaying the anxiety of the girls chemically, we might perhaps settle the school a little bit more, and give the staff an opportunity to put their own house in order…”

‘Not the solution’

Again, Dr Mason supported the plan.

The papers in the the National Archives show she wrote: “I think this sounds a valuable treatment approach to the very real problems that arise from the special nature of girls in residence and in particular the problems presented by younger immature disturbed adolescent girls.”

Shelagh Sunner
The former headmistress at Springhead Park says she did not see the proposed trial as a solution

The files also show that Shelagh Sunner, headmistress of the school between 1966 and 1982, did not support the trial.

Speaking to the BBC about the National Archives material, she said drugs were not the solution for “her” girls.

“They weren’t mentally sick kids” she said. “They needed to work through their emotions”.

The trial did not take place after the school’s managers blocked it, worried about what the girls’ parents would think.

Ms Sunner said she was not surprised, though, that the Home Office endorsed it.

“I think they were scratching their head about what they were going to do with this generation of maladjusted kids – because the approved schools were full and there were a lot of them.”

FDA: Stop Blood Donations, Boost Zika Testing in Florida

The recent Zika cases in Florida has prompted the FDA to recommend that facilities in Miami-Dade County that collect blood stop doing so until further testing can take place.
Researchers are currently assessing the effectiveness of two new educational tools that may help healthcare providers discuss the risks of opioid use with emergency department patients.

A recent study revealed that patients with hepatitis C who also receive ongoing treatment for opioid addiction had high rates of sustained virologic response on elbasvir-grazoprevir.
Researchers reported that seven factors are key to predicting older adults’ pneumonia risk.
The FDA has issued a warning that fluoroquinolone antibiotics may come with serious risks and should be used with caution.

Molecular Imaging Tracks Lung Cancer Immunotherapy

Programmed death ligand (PD-L1) expression in tumors may predict response to checkpoint blockade therapy, but tissue samples are not always on hand to guide therapy. Imaging specialists have addressed this issue by developing and evaluating techniques for non-invasive imaging of PD-L1 expression in tumors.

“Non-invasive imaging of therapeutically effective PD-1 [programmed death 1] and PD-L1 antibodies is of high interest for preclinical and potentially also for the clinical development of these drugs, as it provides an elegant opportunity to obtain quantitative and kinetic information on the whole-body biodistribution of these antibodies, including parameters such as tumor accumulation and blood half-life,” explained Gabriele Niedermann, MD, PhD, of the German Cancer Research Center in Heidelburg, and colleagues, writing recently in Theranostics.

Niedermann’s group developed radiotracers, based on therapeutic checkpoint-blocking antibodies, that allowed for high-resolution PET imaging of both PD-1 and PD-L1 in immunocompetent mice. This “immunoPET” of naïve mice showed similar overall expression patterns for PD-1 and PD-L1 in secondary lymphoid organs (spleen and lymph nodes).

The research also found that PD-L1 tracer uptake was reduced in PD-L1 knockout tumors, and that monitoring the expression changes of PD-L1 in response to its main inducer, the effector T cell cytokine IFN-γ, revealed “robust upregulation in the lung.”

“This suggests that T cell responses in the lung, a vital organ continuously exposed to a variety of antigens, are strongly restrained by the PD-1 checkpoint. In turn, this could explain the association of PD-1 checkpoint inhibition with potentially fatal immune-mediated pneumonitis and partially also its efficacy in lung cancer,” Niedermann and colleagues wrote.

In another animal-model study, Samit Chatterjee, PhD, of Johns Hopkins University in Baltimore, and colleagues performed SPECT-CT imaging, biodistribution, and blocking studies in NSG (NOD scid gamma) mice bearing tumors with constitutive PD-L1 expression (CHO-PDL1) and in controls (CHO).

The preclinical evaluation of a humanized radiolabeled anti-PD-L1 antibody showed specific and increased uptake of radioligand in CHO tumors with stable PD-L1 expression compared with control CHO tumors. The results were confirmed in NSCLC xenografts with varying levels of PD-L1 expression, and in triple-negative breast cancer.

“Subcutaneous NSCLC xenografts showed specific uptake in H2444 tumors compared to H1155 tumors,” the researchers wrote.

They explained that the clinical utility of this antibody imaging agent and others would be to use the radiolabeled antibody accumulation in the tumors to guide therapeutic antibody dosing, and correlate that uptake with tumor response.

“This could be used to establish a relationship between tumor PD-L1 status and therapeutic response, which may have prognostic implications.”

Can these results be translated into humans? Yes, according to Jill Fredrickson, PhD, of Genentech in South San Francisco, and colleagues, who utilized FDG-PET-CT imaging to evaluate atezolizumab (Tecentriq) response among chemotherapy-naïve and previously treated stage IIIB/IV non-small cell lung cancer (NSCLC) patients.

Atezolizumab was developed by Roche, the owner of Genentech, and was grantedpriority review by the FDA in April 2016 for the treatment of locally advanced or metastatic NSCLC with PD-L1 expression.

Fredrickson’s group suggested that patients with NSCLC undergoing immunotherapy may benefit from FDG-PET imaging to assess their disease and predict treatment response, presenting the results of their multinational study at the 2016 Society of Nuclear Medicine and Molecular Imaging Annual Meeting.

Atezolizumab inhibits activity between the PD-1 receptor expressed on certain immune cells and PD-L1, leading to enhanced T-cell priming and re-invigoration of suppressed immune cells.

The primary endpoint of the phase II study was objective response rate on the basis of modified immune-related response criteria. Patients underwent single-time-point FDG-PET scanning — 60 minutes of radiotracer uptake prior to imaging — at baseline, at the time of first tumor assessment during week 6 of immunotherapy, and at disease progression.

Fredrickson and colleagues also wanted to determine if the PET modality and its FDG radiotracer could distinguish between radiographic pseudo progression — an increase in apparent tumor burden due to an anti-tumor T-cell response – from true disease progression.

The study enrolled 138 patients at 28 clinical sites in 5 countries, with 103 patients providing evaluable PET scans at baseline and a post-baseline time point. All patients received 1,200 mg of atezolizumab intravenously every 3 weeks. The scans were analyzed using European Organization for Research and Treatment of Cancer (EORTC) criteria.

Patients with metabolic response by EORTC criteria on scans at week 6 had a higher overall response rate (73.9%) than metabolic non-responders did (6.3%). A patient’s whole-body metabolic tumor volume at the FDG-PET baseline scan was found to be a significant negative prognostic maker for overall survival. A further increase of tumor volume at the 6-week scan was also a sign of decreased overall survival.

The researchers noted that response after apparent radiographic progression was seen in only two patients, so the utility of FDG-PET to distinguish pseudo from true progression could not be determined.

“The utility of FDG-PET in patients with NSCLC on immune blockade therapy appeared to be similar to what has been reported with conventional chemotherapeutic treatments, with early metabolic response predicting subsequent benefit,” the team concluded.

“This study is the first to prospectively evaluate FDG-PET imaging in a phase II trial of lung cancer patients receiving the novel immune checkpoint inhibitor atezolizumab,” Fredrickson said in a press statement. “These findings help define the potential role of FDG-PET as a prognostic and predictive biomarker in the treatment of lung cancer with such immunotherapeutics.”

Worse MI Outcomes for the Poor?

More adverse events after discharge in dual Medicare-Medicaid eligibles.

After being hospitalized for a myocardial infarction (MI), patients with dual Medicare-Medicaid eligibility fared worse than their Medicare-only peers following discharge, investigators found.

Adherence to medication after MI was low in both groups, though patients eligible for Medicare and Medicaid — and therefore of lower socioeconomic class by definition — hadbetter adherence to their medications at 1 year (36.4% versus 30.0% for patients only on Medicare, HR 1.55, 95% CI 1.39-1.74), according to Jacob A. Doll, MD, of Duke University School of Medicine in Durham, N.C., and colleagues in their analysis of Medicare data published online in JAMA Cardiology.

Their dual eligibility, however, was also linked to greater risks:
Readmission at 30 days (HR 1.16, 95% CI 1.06-1.26)
Death at 1 year (HR 1.24, 95% CI 1.14-1.36), and
Major adverse cardiac events at 1 year (HR 1.21, 95% CI 1.12-1.31)
These patients “had worse short- and long-term outcomes after MI despite the additional financial support provided by Medicaid,” the investigators wrote. “While prior studies have shown a similar association between low socioeconomic status and worse outcomes, the present study is novel in demonstrating higher rates of postdischarge medication adherence among patients with dual eligibility, presumably owing to the lower copayment burden in this population.”
What’s more, according to the authors, treatment of the dual-eligibles appeared to be of poorer quality, at least according to objective metrics. Examples include “lower rates of reperfusion for ST-segment elevation myocardial infarction, revascularization for non-ST-segment elevation myocardial infarction, drug-eluting stent (DES) use, and prescription of evidence-based medications at discharge,” they wrote.
“[T]here may be a perception among clinicians that dual-eligible patients are less likely to adhere to medications owing to cost. This may contribute to lower usage rates of revascularization and DES, owing to concerns about discontinuation of dual-antiplatelet therapy,” Doll and colleagues wrote.
“Our analysis indicates that these concerns should not be limited to the dual-eligible population. Nonadherence is common for all patients, and interventions to improve adherence should be applied uniformly.”

“Most notably, the findings counter the stereotype that patients of lower financial means are less adherent to their medications,” according to Ian M. Kronish, MD, MPH, of Columbia University Medical Center/New York-Presbyterian Hospital, who was not involved in Doll’s study.
“So long as generous prescription cost subsidies are in place, low income status was not a risk factor for nonadherence. That said, medication nonadherence was common across all income levels, and remains an important target for post-MI quality improvement efforts,” Kronish told MedPage Today.
Doll and colleagues’ retrospective analysis included 17,419 Medicare patients, 27% of whom were dual eligible.
This subgroup was more likely to be female, nonwhite, and have a higher prevalence of comorbidities. Patients in this cohort were also more likely to present with non-ST-segment elevation myocardial infarction. The hazard ratios reported in the study reflected adjustments for these factors and for in-hospital treatment differences.
Doll’s group acknowledged that the investigation was hindered by its retrospective nature and its inherent caveats, among them unmeasured confounders and missing key information — such as pill counts and specific level of financial assistance given to each patient — that would have provided more precise data on medication adherence and socioeconomic status.
Even so, their study “highlights the fact that failure to prescribe optimal medical therapy for dual eligible patients may partially underlie disparities in post-MI outcomes, and that interventions to reduce disparities in post-MI treatment are in order for dual-eligible patients,” Kronish said.
“Prior studies have clearly shown that physicians are terrible at guessing which of their patients is nonadherent to treatment.”
“Future studies should assess the extent to which conscious and unconscious biases based on income status influence physician estimations of their patients’ adherence status, and whether these biases, in turn, adversely influence physician management of post-MI patients,” he suggested.

Absorb Stent Works Below the Knee

‘Excellent’ results but only in unusually focal lesions.

Implanting the Absorb bioresorbable vascular scaffold in focal below-the-knee lesions was safe and effective in the long run, investigators suggested.

Technical success was achieved in all cases. And the majority of tibial and distal popliteal lesions treated with the everolimus-eluting disappearing scaffold improved at 1 year (79%), Ramon L. Varcoe, MBBS, MS, PhD, of Australia’s Prince of Wales Private Hospital, and colleagues reported online in JACC: Cardiovascular Interventions.

On Kaplan-Meier analysis, primary patency was observed in 96% and 84.6% of lesions at 12 and 24 months, respectively; freedom from clinically-driven target lesion revascularization was 96% at both time points. There was a 6% rate of binary restenosis over follow-up, the authors found.
They concluded that the numbers “demonstrated excellent safety, patency, and freedom from target lesion revascularization using the Absorb bioresorbable vascular scaffold below the knee.”
“It has significant potential to become the favored class of therapy in this group of patients,” they wrote.
“We congratulate the authors for reporting the long-term clinical outcome of their experience with coronary scaffolds in below-the-knee interventions; their restenosis rate, together with the appropriate duration of clinical follow-up, actually represent a proof of concept of the great potential of vascular scaffolds in peripheral interventions,” Antonio Micari, MD, PhD, and Roberto Nerla, MD, both of Maria Cecilia Hospital in Italy, wrote in an accompanying editorial.
Varcoe’s study included 33 patients with critical limb ischemia (68.4%) or severe claudication (31.6%). Operators treated 43 lesions with 50 Absorb scaffolds in total; five patients died over the follow-up period, leaving 38 treated limbs available for analysis.

Importantly, the investigators selected highly focal lesions for their study. The average lesion clot was just 19.2 mm long.
“This makes it impossible to derive reliable considerations about the usefulness and the real impact (in clinical practice) of these devices on below-the-knee procedures, given that infrapopliteal disease is known to be more diffuse and complex in a real-world setting,” according to Micari and Nerla, who suggested that future studies include a broader population.

Biologics Seem to Protect Against Sepsis in RA

Sepsis risk spikes with discontinuation of biologics.

Patients with rheumatoid arthritis (RA) who were being treated with biologic therapies and developed serious infections had a lower risk of sepsis than if they were on conventional agents, German researchers reported.

Among patients on biologics at the time of the infection, the risk of sepsis was almost halved, with an odds ratio of 0.56 (95% CI 0.38 to 0.81), according to Anja Strangfeld, MD, of the German Rheumatism Research Center in Berlin, and colleagues.

Sepsis results from a dysregulation of the inflammatory response following exposure to an infectious agent. It “is a major concern in patients with serious infections because it results in a case fatality rate of 30 to 50%. Older patients are particularly susceptible to sepsis because of hospitalization, comorbidity, and impaired physical function,” the researchers wrote in the September Annals of the Rheumatic Diseases.
Patients with RA are at increased risk of infections, and this is further elevated by the use of immunosuppressive therapies — including biologics — as well as disease comorbidities and complications of joint surgeries.
Several decades ago it was shown that tumor necrosis factor (TNF) was a key player in the cascade of events comprising sepsis, but early clinical trials using TNF inhibitors found no survival benefit, until an animal study suggested that the timing of anti-TNF exposure was crucial for ensuring survival following infection.
None of the earlier trials examined whether being on TNF inhibition at the time of serious infection influenced progression to sepsis, either aiding in recovery or worsening the risk. Therefore, Strangfeld and colleagues analyzed outcomes from the German biologics register, which had enrolled more than 12,000 patients on biologics or conventional disease-modifying anti-rheumatic drugs (DMARDs) by 2013.
Among the cohort, 1,017 serious infections were reported, with the most common being pneumonia, in 28.4%, bone and joint infections in 11.2%, and respiratory tract infections other than pneumonia in 10.3%.

A total of 11.7% progressed to sepsis within 1 month, and the case fatality rate was 63%. Among the patients whose infections did not lead to sepsis, the fatality rate was 6.2%.
Compared with the register cohort in general, patients who developed serious infections were older, had longer duration of disease and greater disease activity, as well as more comorbidities.
In a generalized estimating equations model, older age was associated with a higher risk of both sepsis (OR 1.41 for each 10 years, 95% CI 1.15 to 1.74) and death (OR 2.47, 95% CI 1.61 to 3.79). Underlying chronic renal disease also was associated with an increased risk of sepsis (OR 1.93, 95% CI 1.19 to 3.14), while heart failure was linked with a significantly higher mortality risk (OR 3.56, 95% CI 1.73 to 7.33).
Compared with conventional DMARDs, treatment specifically with a TNF inhibitor at the time of infection lowered the risk of sepsis (OR 0.64, 95% CI 0.42 to 0.97) and death (OR 0.48, 95% CI 0.24 to 0.95). Treatment with other biologic agents also was protective against sepsis (OR 0.45, 95% CI 0.25 to 0.80) and mortality (OR 0.16, 95% CI 0.05 to 0.54).
“The effective immunosuppression via biologic DMARDs may prevent an unregulated host response to serious infection and the development of sepsis,” Strangfeld and colleagues stated.

The researchers then compared outcomes among patients who had not previously received a biologic at the time of the infection (n=134), those who were on a biologic (n=517), and those who had been on a biologic but stopped it more than a month before (n=212).
There were 133 serious infections in the biologics-naive group, 515 in the current biologics group, and 211 in the biologics-discontinued group. Sepsis developed in 17.3% of the biologics-naive group and in 18.4% of the biologics-discontinued group, compared with 11.3% of patients currently on biologics.
After adjustment for age, sex, steroid dose, physical function, and comorbidities, the odds ratios for sepsis (OR 0.97, 95% CI 0.56 to 1.70) and death (OR 0.96, 95% CI 0.42 to 2.17) among those who had discontinued biologics did not differ from those who had never received a biologic.
In contrast, the adjusted risk for sepsis (OR 0.57, 95% CI 0.34 to 0.97) and death (OR 0.34, 95% CI 0.15 to 0.80) was significantly lower for those currently receiving a biologic compared with those never given biologics.
The impact of discontinuation of biologic therapy on sepsis was an important finding of the study, according to the authors.

“It is common knowledge that initiation of biologic DMARD therapy increases the risk of serious infections. Further, discontinuation of biologic DMARDs is supposed to decrease the risk of serious infection,” they wrote.
“Our results suggest a different mechanism: adverse outcomes of serious infections (sepsis and death) were more likely in biologics-naive patients than in patients exposed to biologic DMARDs at the time of serious infection, which could indicate a protective effect of biologic DMARDs,” they explained. But that protective effect was lost when biologics had been stopped, they pointed out.
“Discontinuation of biologic DMARDs seems to shift the risk from an increased susceptibility to serious infections to more severe outcomes,” they observed.
However, the results of this study need to be confirmed.
A limitation of the study was the possibility of “suspicion bias,” with patients on biologic therapies possibly being hospitalized more quickly and followed more closely if they developed serious infections.

CDC Tells Moms-to-Be to Avoid Miami Beach

Miami Beach cases confirmed, CDC moves to contain outbreak.

The CDC has confirmed reports of active Zika transmission in the Miami Beach area of Florida, and has issued updated travel guidance for that particular area.

The area encompasses 1.5 square miles, between 8th and 28th streets of Miami Beach. This is the second cluster of cases in Florida where mosquito-borne transmission appears to be ongoing, and not just isolated cases.

 Pregnant women should now avoid travel to the area of Miami Beach, similar to the guidance already issued for the Wynwood area north of Miami (both in Miami-Dade County). The CDC is also recommending that pregnant women who have traveled to or live in this area of Miami Beach since July 14, 2016 should be tested for Zika virus, and engage in appropriate precautions for the duration of pregnancy.

According to a statement issued by the state of Florida, 36 cases of local Zika virus transmission have been identified in the state.

“Following today’s news, I am asking the CDC for an additional 5,000 Zika antibody test kits to ensure we can quickly test people for the virus and additional lab support personnel to help us expedite Zika testing,” said Florida Gov. Rick Scott (R) in a statement. “Also, to continue protecting pregnant women, I am renewing my call to the Obama Administration for an additional 10,000 Zika prevention kits.”

But the CDC noted in a press release that it has been difficult to detect local spread of Zika, because the incubation period can be up to two weeks, with diagnosis and investigation of cases taking several weeks — as well as that a large portion of people with Zika virus appear asymptomatic.

CDC director, Tom Frieden, MD, also warned that this is not over. “We’re in the midst of mosquito season and expect more Zika infections in the days and months to come,” said Frieden in a statement. “It is difficult to predict how long active transmission will continue. Florida and Miami-Dade County are taking appropriate steps to control mosquitoes and protect pregnant women.”

 The organization acknowledged that it is possible other neighborhoods in Miami-Dade County may also have local Zika transmission — investigators have been probing cases in several areas outside the Wynwood district — but this has not been confirmed.

In addition to the two clusters in Wynwood and Miami Beach, there have also been isolated cases identified in the Miami-Dade County area. The CDC is recommending that pregnant women and their partners who may be concerned about Zika virus may consider postponing travel to Miami-Dade County entirely.

“There have been multiple instances of indidivudal transmission in an area with more than 2 million residents and more than 20,000 pregnant women,” said Frieden during a conference call with reporters. “That’s why we’ve highlighted that while we’re quite concerned about these two areas, we’re mentioning the fact that there have been isolated cases throughout Miami-Dade County.”

Mosquito control may also be more difficult in Miami Beach, where the many high-rise buildings prevent aerial spraying. Frieden said that aerial spraying in the Wynwood area has been more successful, but it has been extraordinarily difficult to eliminate what he characterized as “the cockroach of mosquitoes.”

“So far, what we’re seeing is what we anticipated — multiple individual instances and some cases of clusters,” said Frieden.

Risk of Some Cancers Rises With Duration of Obesity

Duration and extent of overweight and obesity in adulthood have been linked with a significantly increased risk of all obesity-related cancers, according to an analysis of Women’s Health Initiative (WHI) data.
A longer overweight duration significantly increased the risk of all obesity-related cancers combined (multivariable-adjusted hazard ratio 1.07 per 10-year increment, 95% CI 1.06 to 1.09). For postmenopausal breast cancer and endometrial cancer, every 10-year increase in adulthood overweight duration was associated with a 5% and 17% increase in risk, respectively, with these rates rising to 8% and 37% after adjustment for degree of overweight.

Over 6,000 cancers were diagnosed during the 12.6-year mean follow-up. After endometrial cancer, the strongest association was noted for kidney cancer (HR 1.16, 95% CI 1.07 to 1.26). There were no significant associations seen for rectal, liver, gallbladder, pancreatic, ovarian, and thyroid cancer.
“The results of this study indicate that overweight and obesity prevention is essential, at any age. If we manage to raise awareness among people and health practitioners that obesity is a risk factor for several diseases, not only cancer, this would be a great success,” lead author Melina Arnold, PhD, of the International Agency for Research on Cancer, Lyon, France, told MedPage Today in an email.
“It’s an important study, and their approach is certainly unique in a good way,” commented Susan Gapstur, PhD, MPH, vice president of epidemiology at the American Cancer Society, who was not involved in the study, in an interview with MedPage Today. “It would be interesting to replicate their findings, and extend this to obesity-related cancers in men as well as African Americans, Asians, and other populations. It is good additional information that may hopefully motivate people to prevent weight gain, even starting in young adulthood.”
With high body mass index supplanting tobacco smoking as the leading contributor to disease burden in high-income countries, and U.S. rates of adult overweight and obesity (currently at about 70% and 36% respectively) continuing to increase, this represents a significant public health concern, wrote Arnold and colleagues, published in PLOS Medicine.
Using data for approximately 74,000 WHI participants who were free of cancer at baseline, and had at least three BMI measurements over time and complete covariate information, researchers employed a quadratic growth model to estimate BMI trajectories across ages. Participants were postmenopausal women 50-79 years old from 40 clinical centers across the U.S., enrolled from October 1993 to December 1998.

Duration of overweight (BMI ≥25), obesity duration (BMI ≥30), and weighted cumulative overweight and obese years, which take into account the degree of overweight and obesity over time (a measure similar to pack-years of cigarette smoking, authors explained), were calculated using predicted BMIs. Cox proportional hazard models were applied to determine the cancer risk associated with overweight and obesity duration.
In secondary analyses, a priori interactions were assessed by stratifying by postmenopausal hormone use, hysterectomy and/or oophorectomy, ethnicity, diabetes, and smoking status.
Of all study participants, 40% were never overweight during adulthood (age 18 years until study exit); of the remaining 60%, average duration of overweight was 31.3 years, and average duration of obesity was 20.6 years.
At baseline, women who were ever overweight or obese, compared with those who were never overweight, were:
slightly younger at baseline
had a lower education
more likely to be African-American
less physically active
consumed more calories and had a lower quality of diet
more likely to report ever being diabetic
less likely to be using postmenopausal hormones
more likely to have had a hysterectomy
Statistical analyses included adjustments for these factors.

“In our study, we found that the risk of postmenopausal breast and endometrial cancers related to overweight and obesity duration differed by postmenopausal hormone use, and was largely attenuated or even absent among users,” the researchers indicated. “This does not mean that obesity does not increase the risk of cancer in women using postmenopausal hormones, as it might have simply obscured its effect. A 2015 study using data from the Women’s Health Initiative suggested a remaining positive association between obesity and cancer risk, independent of postmenopausal hormone use.”
The researchers noted several study limitations: BMI is not an ideal measure for body fat since it does not differentiate fatty tissue from lean tissue and bone; retrospective self-reports of BMI may be subject to error; and non-Hispanic white women comprised 84% of the study population.
Arnold told MedPage Today, “Given a similar overweight prevalence in this cohort of women when compared to the general U.S. population, we believe that our findings are generalizable to the female U.S. elderly population and potentially to other high-income countries experiencing similar levels of overweight and obesity.”

Gender No Predictor of Prolonged DAPT Benefit

Prolonged dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI) effects don’t differ by gender, the PRODIGY investigators suggested.

On multivariable adjustment, recipients of extended and 6-month DAPT experienced similar rates of combined death, myocardial infarction, and cerebrovascular accidents at 2 years. This was true whether they were male (HR 1.08, 95% CI 0.766 to 1.522) or female (HR 1.013, 95% CI 0.588 to 1.748), reported Marco Valgimigli, MD, PhD, of Bern University Hospital in Switzerland, and colleagues.

 According to their study, published online in JACC: Cardiovascular Interventions, sex did not appear to play a role in the frequency of individual adverse outcomes. Notably, major bleeding occurred at similar rates across groups regardless of the definition used (included were the Bleeding Academic Research Consortium, Thrombolysis in Myocardial Infarction, and Global Use of Strategies to Open Occluded Coronary Arteries scales).

“Gender failed to emerge as a treatment modifier with respect to DAPT durationsuggesting that the decision-making on DAPT duration in female patients should weigh ischemic versus bleeding risks,” the authors concluded.

They noted that the longer duration won out in the landmark DAPT trial likely because of the selection of endpoints — stent thrombosis and the combination of MI and stroke.

While the secondary analysis of the PRODIGY trial, which randomized 1,970 patients to 6- or 24-month DAPT consisting of clopidogrel (Plavix) and aspirin, was only powered to find a 40% difference, it was in line with other trials that haven’t shown a significant impact on death or cardiovascular death, the researchers noted.

“When taken together, currently available studies suggest that the decision-making over DAPT duration towards either shorter or longer than conventional 12-month time frame should be a ‘patient by patient’ approach, aiming at balancing ischemic versus bleeding risks,” they concluded. “With that respect, whether gender per se should be taken into account in tailoring patient’s therapy is still unclear.”

 But what was clear from PRODIGY was that “gender should not be a primary covariate to be considered in the decision-making on DAPT duration after coronary stenting,” they added.

In the trial, women (n=459) were older and more likely to have hypertension, lower creatinine clearance, and acute coronary syndrome. Men, however, had a higher severity of coronary artery disease.

“The current findings suggest that men and women undergoing PCI have similar adjusted 2-year ischemic and bleeding outcomes, despite being characterized by different clinical presentation,” according to Valgimigli’s group.

Does Prenatal Acetaminophen Use Affect Kids’ Behavior?

Link between risk of behavioral problems, use of drug.

Prenatal exposure to acetaminophen was linked with a subsequent increased risk of behavioral problems in children, even after controlling for multiple confounders, a small cohort from a U.K. study found.

Maternal use of acetaminophen especially during the third trimester (32 weeks) was associated with a higher risk of conduct disorders, emotional problems, and problems with hyperactivity when children were 7 years old, reported Evie Stergiakouli, PhD, of University of Bristol in the U.K., and colleagues.

 Notably, these associations remained, even after adjusting for a variety of confounders, including both maternal prenatal and postnatal acetaminophen use, as well as genetic factors — such as an index of ADHD genetic risk in mothers. Overall, 5% of children had behavioral problems.

“[This] suggests that the association … is not explained by unmeasured familial factors linked to both acetaminophen use and childhood behavioral problems and that the findings are consistent with an intrauterine effect,” the researchers wrote. “Our results could have important implications for public health advice, which currently considers acetaminophen safe to use during pregnancy.”

Writing in JAMA Pediatrics, the authors analyzed data from the U.K. prospective birth cohort, the Avon Longitudinal Study of Parents and Children (ALSPAC), which enrolled 7,796 pregnant women from 1991 to 1992. Among those women 53% used acetaminophen during the third semester and 42% used the drug in the second semester.

The authors found that the risk of emotional and hyperactivity problems was also associated with acetaminophen use in the second trimester (18 weeks), though the risk was slightly lower than use of the drug in the third trimester.

Overall, maternal prenatal acetaminophen use in the third trimester was linked with an increased risk of several maternal-reported behavior problems in children from theStrengths and Difficulties Questionnaire, including:

  • 46% higher odds of “total difficulties” (RR 1.46, 95% CI 1.21-1.77)
  • 42% higher odds of conduct problems (RR 1.42, 95% CI 1.25-1.62)
  • 31% higher odds of hyperactivity symptoms (RR 1.31, 95% CI 1.16-1.49)
  • 29% higher odds of emotional problems (RR 1.29, 95% CI 1.09-1.53)

Second trimester use was linked with 23% higher odds of hyperactivity symptoms and 20% higher odds of conduct problems.

The authors argued that the timing of the drug might be important, with prior researchalso showing stronger associations between risk of behavioral problems and maternal acetaminophen use in the third trimester, as opposed to the second trimester.

“Given that there is active brain development and growth during the third trimester, this finding could indicate that there are developmental periods when the brain is more sensitive to acetaminophen exposure,” they wrote.

There are several hypotheses for the mechanisms surrounding the effect acetaminophen use may have on fetal neurodevelopment, including the endocrine-disrupting properties of the drug or the disruption of brain development through oxidative stress.

“Further studies are required to elucidate mechanisms behind this association as well as to test alternatives to a causal explanation,” the authors concluded.