Former Rugby Internationals to Take Part in Concussion Study


More than 100 former rugby internationals have agreed to take part in a unique scientific study on the effects of concussion on brain health to increase player safety standards in the sport, the Rugby Football Union (RFU) has said.

The issue has long been a source of concern in rugby and resurfaced last month when England captain Dylan Hartley, sidelined for 14 weeks with various head injuries last season, said he would consider retirement if he suffered another concussion.

“We want to be able to give players detailed information about the consequences of suffering three, four or five concussions,” Dr Simon Kemp, the RFU’s chief medical officer, told the Times.

“It is not something we can do with any evidence base at the moment. The majority are uncomplicated in the short-term but five or 10 percent need extended recoveries like Dylan’s was, and then this study will look at the long-term effects.”

More than 200 former players, aged over 50, who reported concussions during their playing days will go through physical and cognitive tests to study possible links between concussion and neurodegenerative diseases such as Alzheimer’s.

Professor Neil Pearce, who will lead the study, said he hoped the results would be conclusive in establishing the long-term effects of concussion.

“Evidence is accumulating on the possible long-term health risks in former contact-sport athletes,” said Pearce, a professor at the London School of Hygiene & Tropical Medicine.

“This study will start to fill this gap, and will allow us to assess whether there are long-term health problems and what their causes may be.”

The study’s findings will be shared with governing body World Rugby as part of ongoing efforts to increase awareness about the subject among players.

New guidelines were introduced at last year’s World Cup, where concussed players were reviewed by an independent doctor before returning to action.

Wearable Artificial Kidney Offers Hope for Dialysis Patients


An experimental wearable artificial kidney shows promise as a substitute for dialysis machines, researchers report.

More than 2 million people worldwide with kidney failure require chronic dialysis. They must follow strict limitations as to what they eat and drink.

Longer, more frequent dialysis would offer better outcomes, but current dialysis machines aren’t portable. They limit patients’ freedom of movement and ability to engage in the normal activities of daily living.

“As a physician who cares for patients with kidney disease, it is my hope that in the future we have something better to offer than we do today for dialysis therapy,” Dr. Jonathan Himmelfarb from the University of Washington in Seattle told Reuters Health.

He would like to see “a treatment that can enhance quality of life, allow for more autonomy and opportunity for full rehabilitation, and possibly to extend life as well, compared to today’s available therapeutic options.”

“We owe it to our patients to do everything we can to make this a reality,” Himmelfarb said by email.

He and his colleagues created a continuously operating wearable artificial kidney that was effective in earlier pilot studies where treatment was limited to 8 hours.
Now they report the results of a 24-hour test of the wearable artificial kidney in 11 patients with end-stage kidney disease who had been on dialysis for an average of 15 months.

Five patients completed the planned 24-hour treatment period, during which the device performed as expected.

There were challenges along the way, though. One patient had to stop treatment because of clotting of the blood circuit. In two patients, the machines needed new batteries before the end of the 24 hours. Three patients had to interrupt treatment to have gas bubbles removed from the blood circuit.

Because of a variety of device-related technical problems, the trial was stopped early, the authors reported in JCI Insight.

There were no serious complications, and all subjects were able to walk around freely while receiving artificial kidney treatment. The patients reported satisfaction with the few side effects, the convenience and flexibility of treatment, the discomfort associated with treatment, and the freedom allowed by the wearable artificial kidney.

The researchers say the technical problems will need to be addressed through device redesign and refinement before further long-term studies can be done.

“We would hope to be able to conduct a follow-up trial beginning sometime in the next several years,” Dr. Himmelfarb said. “It will be a number of years before such a treatment can be proven safe and effective, and be readily available to patients living with kidney disease.”

Dr. Karin Gerritsen and Dr. Jaap Joles from University Medical Center Utrecht in The Netherlands, who recently reviewed the current status of wearable kidney development, told Reuters Health by email, “Wearable and portable artificial kidneys are certainly on the horizon, but it will still take a few years before they become widely available.”

“The device may be a very good alternative for daily (nighttime) hemodialysis while operating in a bedside mode,” they said. “This would already be a great step forward compared to conventional in-(clinic) hemodialysis three times a week.”

Renal Replacement Therapy — Sooner or Later?


Initiation Strategies for Renal-Replacement Therapy in the Intensive Care Unit

 

Summary

Acute kidney injury (AKI) is a common and challenging condition to manage in critically ill patients, with many studies over the past decade attempting to better define, characterize, and optimize treatment. In particular, the timing of renal replacement therapy (RRT) in critically ill patients with AKI remains contentious.[1,2]

Gaudry and colleagues sought to determine whether earlier or later initiation of RRT would result in better outcomes in patients who were either mechanically ventilated or on vasopressors (or both) but without an acute indication for dialysis.[3] They randomly assigned 620 patients to initiate RRT either earlier (at randomization) or later (when an acute indication for dialysis arose).

There was no overall difference in 60-day mortality (48.5% vs 49.7%), and 49% of patients in the delayed group never initiated RRT. Catheter-related bloodstream infections were more frequent in the early RRT group (10% vs 5%; P=.03), and diuresis occurred earlier in the delayed RRT group.

The authors concluded that there was no difference in mortality with earlier RRT and that a delayed strategy often averted the need for RRT.

Viewpoint

The major finding of this study is there are no differences in major clinical outcomes attributable to the timing of RRT initiation in critically ill patients, at least in those with the most severe AKI (Kidney Disease: Improving Global Outcomes [KDIGO] classification stage 3)[4] who are mechanically ventilated or on vasopressors (or both). Although those qualifiers could make a difference, it seems unlikely that the timing of RRT initiation would produce substantially better outcomes in different intensive care unit populations, such as patients with less severe AKI or those not on vasopressors.
Regardless, it appears that delayed initiation of RRT is superior in some respects. For example, at the individual patient level, delayed RRT resulted in earlier and more significant urine output (shown in this study particularly as a greater probability of adequate urine output). And from the perspective of providers and health systems, delayed RRT resulted in less use of dialysis by half. For critically ill patients with severe AKI, delayed initiation of RRT is appropriate, pending the development of an indication for more acute initiation.

Talk to Neuro Patients About Stress, Sleep, and Sex


Patients with a neurologic disorder often also have psychiatric symptoms or other problems affecting their quality of life, underlining the importance of looking beyond the neurologic diagnosis.

A special session on stress, sleep, and sexual dysfunction looked at the broader picture of neurological disease here at the Congress of the European Academy of Neurology (EAN) 2016.

Ideally, neurologists would screen all their patients for psychiatric symptoms by using such tools as the Brief Symptom Inventory (BSI), Christian Schmidt-Kraepelin, MD, Department of Psychiatry and Psychotherapy, Heinrich-Heine-University, Düsseldorf, Germany, told his audience, many of them residents and young neurologists.

“It only takes about 15 minutes to do and most patients are relieved to be able to talk about these things.”

He also recommended that graduating neurologists work at a psychiatric hospital for a year. “This would give you the option to learn a lot more about psychotherapy and how to build up a good patient relationship.”

For example, he said, neurologists in Germany routinely get 1 year of training in psychiatry, which is not the case elsewhere.

Co-occurring Disorders

In clinical practice, psychiatric disorders and neurologic disorders commonly co-occur. But patients are typically treated by either a neurologist or a psychiatrist and rarely by a neuropsychiatrist, or someone trained in both specialties, Dr Schmidt-Kraepelin said.

This, he said, increases the chance of a psychiatric condition going unrecognized and untreated.

In his own department of neuropsychiatry, Dr Schmidt-Kraepelin and his colleagues have developed a neuropsychiatric screening procedure. Patients complete the BSI and the Hospital Anxiety and Depression Scale, with reports containing recommendations being sent to the treating neurologist.

At this meeting, he reported results from 602 patients who completed this procedure.

The extent of psychiatric comorbidity is high. For example, among patients with degenerative disorders, such as Parkinson’s disease (PD) and Alzheimer’s disease (AD), 17.2% had phobic anxiety and 15.5% had anxiety.

Of those with epileptic disorders, 13.8% had phobic anxiety and 13.0% had paranoid ideation.

And of those with demyelinating disorders, 20.3% were experiencing anxiety, 18.8% had depression, and 17.2% had obsessive-compulsiveness.

It’s sometimes difficult to determine whether the psychiatric symptoms are a direct effect of the underlying neurologic disorder or whether there are “reactive factors,” said Dr Schmidt-Kraepelin.

In any case, stigmatization is still a problem among neurology patients with psychiatric symptoms. “There are stereotypes that are still out there in the patient population, and also among neurologists.”

He says his own neurology colleagues are averse to asking patients about suicidal thoughts for fear that patients would feel offended or stigmatized.

“We as psychiatrists ask this question 20 to 30 times a day; it’s not such a taboo thing from our experience because many patients feel relieved” when asked about suicidal thoughts, he said.

 His message to young neurologists, he said, is to personally “get to know your colleagues” from psychiatric departments. “This makes it a lot easier to communicate about patients and to get to know the treatment options.”

Sleep Issues

During the same session, Wolfgang Oertel, MD, professor, neurology, and director, Department of Neurology, The Philipps University, Marburg, Germany, addressed sleep issues among patients, including those with neurologic conditions.

 Sleep disorders, he said, are not uncommon. The most prevalent — insomnia — affects some 10% of the population, with obstructive sleep apnea occurring in 1% to 2%. Restless legs syndrome (RLS) affects 5% to 10% of the population, with up to 3% needing therapy.

The quality of life for patients with RLS is “terrible,” said Dr Oertel. Drugs available for this condition only block one dopamine receptor but two are involved in RLS. However, with ongoing research on genetic contributions to this condition, and work on developing an agonist for both dopamine receptors, there’s hope that new drugs will soon be available for these patients, said Dr Oertel.

He noted that another sleep disorder — rapid-eye-movement sleep behavior disorder (RBD) — is linked to PD. About 85% of patients with RBD, a condition that involves dream-enacting behavior and aggressive dream content, develop PD, he said.

 For most patients, getting 7 hours of sleep every night is “key,” said Dr Oertel. The consequences of the brain not sufficiently recharging may be more than just an increased risk for fatigue and accidents. Some research is looking at the role of sleep in the formation of memory and the possibility of a connection between sleep deprivation and AD.

Sexual Issues

Finally, in a separate presentation here, David B. Vodušek, MD, PhD, professor, neurology, University of Ljubljana, Slovenia, addressed sexual dysfunction among neurology patients. He stressed the need for teaching communication skills to medical students and residents and the importance of compassion and “shared respect” in the doctor–patient relationship.

 Patient-centered care, said Dr Vodušek, means considering the patients’ fears and values as well as their symptoms. Sexual complaints can have a major impact on quality of life. He advises that doctors routinely obtain a patient’s sexual history.

All speakers agreed that building trust is a crucial element to the doctor–patient relationship, and this effort doesn’t need to be hugely time-consuming. It might, for example, just mean refraining from interrupting patients when they describe their stress or sleep issues, or being careful of body language, whether that is refraining from standing over them in a paternalistic stance or using simple techniques, such as sitting next to them and looking them in the eye.

Empagliflozin Slows Progression of Renal Disease in Diabetes


New data from the EMPA-REG OUTCOME trial with the sodium-glucose cotransporter-2 (SGLT2) inhibitor empagliflozin (Jardiance, Boehringer Ingelheim) show that the drug significantly reduced the incidence of worsening nephropathy by 39% in the population of type 2 diabetes patients studied (ie, those who were at high cardiovascular risk).

The results were received to spontaneous applause here today at the American Diabetes Association (ADA) 2016 Scientific Sessions when presented by nephrologist Christoph Wanner, MD, of the Würzberg University Clinic, Germany; they were also simultaneously published in New England Journal of Medicine with Dr Wanner as lead author.

The assessment of renal outcomes in EMPA-REG was a prespecified outcome of the trial, Dr Wanner noted, and he added that the beneficial effects on the kidney observed in the trial “were there early and continued for the whole of the study.” Moreover, these effects were observed with both doses of empagliflozin employed (10 mg and 25 mg once daily).

“Empagliflozin reduced clinically relevant renal events when added to standard of care in patients with type 2 diabetes and high cardiovascular risk,” he announced, adding that this effect was primarily driven by a reduction in new-onset macroalbuminuria (hazard ratio [HR], 0.62 for those treated with empagliflozin compared with placebo; P < .001).

He pointed out that kidney disease is “a growing concern” in patients with type 2 diabetes, with 35% of patients eventually developing it, and noted that almost half (44%) of the renal-dialysis population at any current time is made up of those with diabetes, primarily type 2.

“In the placebo group you see the natural progression of kidney disease [as would be expected in type 2 diabetes] whereas the [estimated glomerular filtration rate] eGFR in the empagliflozin group remained stable,” he observed.

Important Addition to Original Findings, but More Work Needed

Dr Wanner noted, however, that the EMPA-REG trial lasted only 3 years, “so we are certainly looking to the future for more on this.”

And both he and discussant of the findings at ADA, endocrinologist and epidemiologist, William Herman, MD, MPH, of the University of Michigan, Ann Arbor, stressed that the results are applicable only “to the population studied in the EMPA-REG trial” (ie, older patients with type 2 diabetes at high cardiovascular risk).

Currently, about a third of the population of type 2 diabetes fall into that category, Dr Herman said.

Nevertheless, Dr Wanner observed in his presentation: “There have been no new diabetic kidney-disease–specific treatments in the past 15 years, until today.”
And he hinted that the agent may well be used in those who don’t yet have overt cardiovascular disease (CVD). “Nephrologists are waiting for this drug for patients with albuminuria,” he told Medscape Medical News.

They and endocrinologists “maybe will not wait until the patient has survived a myocardial infarction — there are some patients without cardiovascular disease but already with nephropathy, so I think we are all going to use this drug in the nephropathy patients with albuminuria.”

But Dr Herman pointed out in his talk that “the absolute differences are relatively small” in EMPA-REG and the number needed to treat with empagliflozin to achieve the renal benefits was 200.

In addition, it’s possible that the findings “had to do with medications not administered,” he said. “So it may not be a benefit of empagliflozin but the fact that those in the empagliflozin group did not receive medications causing harm [as patients in the trial were also allowed certain other standard therapies for diabetes].”

Overall, as well as the demonstrated renal effects, empagliflozin is “moderately effective” at lowering HbA1c and results in a 2- to 3-kg reduction in body weight, with no issue with hypoglycemia, although it does increase the risk of genitourinary infections, Dr Herman surmised.

He concluded that empagliflozin is “a reasonable therapy, but we still don’t know its exact role or exact mechanisms of action.”

Chair of the session in which the EMPA-REG renal findings were presented at ADA, Matthew Riddle, MD, from Oregon Health & Science University, Portland, said the renal outcomes from EMPA-REF are “an important addition to the original findings,” which nevertheless require further analysis.

Cost Is a Huge Issue

Of key importance, said both Drs Herman and Riddle, is the fact that empagliflozin and other SGLT2 inhibitors — like the other newer agents for type 2 diabetes (dipeptidyl peptidase-4 [DPP-4] inhibitors, glucagonlike peptide-1 [GLP-1] agonists, and insulin analogues) —are expensive, costing, in the US, in the region of $500 per month, as compared with a few dollars for metformin, the recommended first-line agent for type 2 diabetes and some other generically available drugs, such as sulfonylureas and pioglitazone.

Another trial with one of these newer agents, the GLP-1 agonist liraglutide (Victoza, Novo Nordisk), stole the headlines here yesterday with the results of the LEADER trial indicating that it significantly reduced the rates of major adverse cardiovascular events in a patient population similar to those in EMPA-REG, type 2 diabetes patients at elevated cardiovascular risk. This has prompted some experts to predict “a new era” in the management of type 2 diabetes.

Dr Riddle, however, believes this is a premature conclusion to draw: “I don’t think the regulatory agencies’ and the professional societies’ recommendations are going to change immediately; we are going to have to digest these findings,” he told Medscape Medical News.

And, he added, “The cost [of newer diabetes drugs] is a huge issue in the US. It’s one of the things I’m very interested in and very disturbed by.

“The range of cost between a generic established evidence-based oral therapy like metformin, the sulfonylureas, and now pioglitazone and the new agents is 100-fold. That is a big increase for, in some cases, a modest theoretical or practical advantage. So it’s a problem for physicians and patients in the US.”

Drilling Down Into Renal Outcomes

In the overall EMPA-REG trial, first reported last September to much acclaim, more than 6000 patients with type 2 diabetes at high risk of cardiovascular events were randomly assigned to one of two doses of empagliflozin or placebo on top of standard therapy. Empagliflozin reduced the risk of major adverse cardiovascular events by 38% relative to placebo.

 In this new analysis of microvascular outcomes, incident or worsening nephropathy occurred in 525 of 4124 patients taking empagliflozin and 388 of 2061 in the placebo group (12.7% vs 18.8%; HR, 0.61; P< .001).

This renal end point consisted of a combination of progression to macroalbuminuria, a doubling of serum creatinine, the start of renal-replacement therapy, or renal death.

However, the benefit was primarily driven by the reduction in new-onset albuminuria, which occurred in 459 of 4091 patients taking empagliflozin compared with 330 of 2033 patients on placebo (11.2% vs 16.2%; HR, 0.62; P < .001).

 Kidney dialysis was also reduced by more than half among those taking empagliflozin, although the absolute numbers affected were small (HR, 0.45; P = .0409).

In an editorial accompanying the renal findings in the published paper, Julie R Ingelfinger, MD, from Massachusetts General Hospital, Boston, Massachusetts, and Clifford J Rosen, MD, from the Center for Clinical and Translational Research, Maine Medical Center Research Institute, Scarborough, say: “This new report indicates that empagliflozin was associated with a slower progression of kidney disease and lower rates of clinically relevant renal events than was placebo when added to standard care in [type 2 diabetes] patients at high cardiovascular risk.”

And commenting on both EMPA-REG overall and LEADER, “We are left with differences that are encouraging yet are not a home run with regard to the management of diabetes,” they point out.

Is Empagliflozin a Renal Drug?

There was also some discussion at the ADA meeting about the mechanism of action of empagliflozin, both in lowering cardiovascular risk and now with regard to these renal benefits.

Most newer agent for diabetes will require dose adjustment in diabetic kidney disease because the majority are renally excreted; this includes DPP-4 inhibitors other than linagliptin, most GLP-1 agonists with the exception of liraglutide, and the SGLT2 inhibitors.

The latter, including empagliflozin, have required dose adjustment in patients with diabetic kidney disease. The current licenses for most SGLT-2 inhibitors precludes their use in patients with renal failure (eGFR < 60 mL/min/1.73 m2 in some cases or < 45 mL/min/1.73 m2 in others).

Dr Wanner said that 25% of the patients in EMPA-REG had eGFR < 60 mL/min/1.73 m2, more than a third already had albuminuria, and almost a third already had prevalent kidney damage.

Yet, paradoxically, they seem to provide some renal protection. These newest findings from EMPA-REG bolster excitement about the potential for SGLT2 inhibitors to provide a renoprotective effect, despite being metabolized by the kidney.

“The effect of empagliflozin on renal outcomes was there early and continued for the whole of the study, with both doses showing an effect. Empagliflozin works at lower stages of kidney function too,” Dr Wanner stressed.

Silvio Inzucchi, MD, of Yale University, New Haven, Connecticut, the lead investigator of EMPA-REG, added also that, regarding the overall cardiovascular benefit of empagliflozin seen in the trial, “there was no heterogeneity of effect based on eGFR; cardiovascular disease was reduced even in stage 3b renal-disease [eGFR 30–45 mL/min/1.73 m2] patients.”

Another SGLT2 inhibitor, canagliflozin (Invokana, Janssen) is being specifically tested in a diabetic kidney-disease population in the large multicenter randomized Evaluation of the Effects of Canagliflozin on Renal and Cardiovascular Outcomes in Participants With Diabetic Nephropathy (CREDENCE) trial.

This will enroll 3000 patients with stage 2 or 3 chronic kidney disease and macroalbuminuria already receiving standard of care. They will be randomized to canagliflozin 100 mg daily or placebo for 5 years, and results are not expected until 2019.

It is not known whether the latest caution from the Food and Drug Administration, strengthening the warning regarding acute kidney injury for canagliflozin and dapagliflozin, will affect this trial. This states that healthcare providers should consider factors that might predispose patients to acute kidney injury prior to starting them on canagliflozin or dapagliflozin.

 

Weight loss before fertility treatment fails to increase birth rate in women with obesity


No difference in birth rates was found among women with obesity assigned to a weight-loss intervention preceding infertility treatment and those assigned to immediate infertility treatment.

“The rates of pregnancy-related, labor-related, and neonatal complications and neonatal outcomes were similar in the two groups. … After exclusion of women who did not complete the intervention program from the intervention group, birth rates and the time to pregnancy were similar in the two groups,” the researchers wrote.

Annemieke Hoek, MD, PhD, of the department of obstetrics and gynecology at the University Medical Center Groningen, University of Groningen, the Netherlands, and colleagues randomly assigned women with obesity (BMI 29 kg/m2) and infertility to a 6-month lifestyle-intervention program followed by 18 months of infertility treatment (intervention group; n = 289) or to prompt infertility treatment for 24 months (control group; n = 285). Participants were from six university medical centers and 17 general hospitals in the Netherlands and identified between June 2009 and June 2012.

Participants in the intervention group had a goal of weight loss of 5% to 10% of body weight from the time of randomization. During a 24-week period, participants attended six outpatient visits and had four telephone consultations in which they were advised to reduce their energy intake by 600 kcal per day and maintain a minimum caloric intake of 1,200 kcal per day. Moderate-intensity physical activity and at least 30 minutes of moderate-intensity exercise two to three times per week also was recommended for the intervention group.

The control group was generally treated with clomiphene citrate at a starting dose of 50 mg per day for 5 days beginning the second to fifth day after natural or progestin-induced menses. Clomiphene citrate was replaced with gonadotropin therapy in a low-dose step-up regimen beginning with 75 IU per day if pregnancy did not occur within six to 12 cycles or clomiphene resistance developed.

Thirty-seven percent of participants in the intervention group lost 5% or more of their original body weight. Mean weight loss was 4.4 kg in the intervention group and 1.1 kg in the control group.

During the 24-month study period, the number of vaginal births of healthy singletons was significantly higher in the control group (n = 100) compared with the intervention group (n = 76); however, there were no significant differences between the groups for rates of vaginal births of healthy singletons or the rates of live births after inclusion of data from pregnancies conceived within 24 months after randomization but delivered after that period.

Median time to pregnancy resulting in vaginal birth of a healthy singleton at term was lower in the control group (5.2 months) compared with the intervention group (7.2 months; P = .06). Similar results were found for pregnancy resulting in a live birth (control group, 5.2 months vs. intervention group, 8.8 months; P = .04).

“A more intensive program or one involving better strategies to enhance adherence might have resulted in more weight loss, but it is unknown whether more weight loss would have led to a higher birth rate than the rate in our trial,” the researchers wrote. “Moreover, excessive weight loss in a short period of time was discouraged, since such reduction in weight has been reported to have a negative effect on the outcome of assisted reproductive technology and to be associated with an increased risk of adverse pregnancy outcomes, such as low birth weight or miscarriage.” – by Amber Cox

Reproductive success linked to 25-(OH)D concentrations in PCOS


Measures of reproductive success in women with polycystic ovary syndrome after ovulation induction may be independently predicted by serum 25-hydroxyvitamin D levels, according to study data.

“Our current study reaffirms a relevance of adequate 25-(OH)D for procreative success in women with PCOS undergoing [ovulation induction],” the researchers wrote. “Beyond reaffirming a consistency in directionality of the previously observed associations, we have additionally noted that this association becomes apparent at serum 25-(OH)D levels that are well beyond the threshold of 30 ng/mL that is currently deemed as a target ‘normal’ level.”

Lubna Pal, MBBS, F RCOG, FACOG, associate chair of education in the department of gynecology and reproductive sciences at Yale School of Medicine, and colleagues evaluated data from the Pregnancy in Polycystic Ovary Syndrome (PPOS I) randomized controlled trial on 540 women (mean age, 28 years) with PCOS to determine whether any links exist between vitamin D status and ovulation induction outcomes.

Primary outcome was live birth, and secondary outcomes included ovulation and pregnancy loss after ovulation induction. Vitamin D status was defined as sufficient ( 30 ng/mL), inadequate (20-29.9 ng/mL), deficient (< 20 ng/mL) or severely deficient (< 10 ng/mL).

During the 6-month trial duration, 74% of participants had evidence of ovulation. Compared with participants with 25-(OH)D levels of at least 20 ng/mL, those with 25-(OH)D deficiency were less likely to achieve ovulation (P = .006).

Live birth rate was nearly 19% overall. Compared with participants who did not deliver a live birth, serum 25-(OH)D was higher in those who did (P = .046). The likelihood of live birth was increased by 2% with each 1 ng/mL increase in 25-(OH)D (OR = 1.02; 95% CI, 1-1.04). Participants who were vitamin D sufficient had a 26% live birth rate, whereas the likelihood of live birth decreased in participants with vitamin D insufficiency (OR = 0.74; 95% CI, 0.57-0.96), vitamin D deficiency (OR = 0.61; 95% CI, 0.35-1.08) and vitamin D severe deficiency (OR = 0.48; 95% CI, 0.19-1.23).

Participants with vitamin D levels greater than 45 ng/mL had a fourfold increased likelihood of live birth (OR = 4.5; 95% CI, 1.27-15.72), whereas there was a 44% reduction in likelihood of live birth among participants with 25-(OH)D levels less than 30 ng/mL (OR = 0.58; 95% CI, 0.35-0.92). There were progressive improvements in the odds for live birth at 25-(OH)D thresholds of at least 38 ng/mL (OR = 1.42; 95% CI, 1.08-1.8) and at least 40 ng/mL (OR = 1.51; 95% CI, 1.05-2.17).

Twenty-nine percent of positive pregnancy tests were followed by pregnancy loss, and there was an 82% reduced likelihood of pregnancy loss with serum 25-(OH)D levels of at least 38 ng/mL compared with lower levels (OR = 0.18; 95% CI, 0.02-0.9).

“Our data suggest that for infertile women with PCOS, [vitamin D] status, as reflected by serum levels of 25-(OH)D, is relevant for procreative success,” the researchers wrote. “We hypothesize that decline in circulating 25-(OH)D below the [lower reproductive threshold] may be contributory to ovulatory dysfunction, whereas at levels at and above an [upper reproductive threshold], achieved through supplementation, may result in improved endometrial receptivity, as has been previously suggested, thus yielding improved treatment [live birth] rates and reduce risk of [pregnancy loss] in women with PCOS, a population that is already an enhanced risk for pregnancy wastage.” – by Amber Cox

Maternal Folate Levels Are Predictive of Child Obesity Risk


Adequate maternal folate levels may mitigate the risk for childhood obesity, especially among children born to obese mothers, according to a study published online June 13 in JAMA Pediatrics.

“In this urban low-income prospective birth cohort, we demonstrated an L-shaped association between maternal plasma folate concentrations and child OWO [overweight or obesity] and the benefit of sufficient folate concentrations, especially among obese mothers,” write Xiaobin Wang, MD, MPH, ScD, from the Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland, and colleagues.

The researchers analyzed data from 1517 mother–child dyads collected from the Boston Birth Cohort, a predominantly urban, low-income, minority population. Participants were recruited at birth from 1998 to 2012 and followed up from birth through 9 years of age (2003 – 2014).

Inclusion of mother–children pairs required at least one postnatal well-child care visit beyond 2 years of age and complete data on maternal folate concentrations and body mass index (BMI). The researchers categorized maternal BMI into three groups: normal weight (18.5 – 24.9 kg/m2), overweight (25 – 29.9 kg/m2), and obese (≥30 kg/m2). Maternal folate levels were collected 2 to 3 days after delivery and used as a surrogate marker for third trimester folate levels. The investigators calculated child BMI z score according to US reference data and defined OWO as a BMI in the 85th percentile or higher for age and sex.

The researchers found an overall nonlinear, inverse association between maternal folate levels and OWO, noting that the risk for OWO was highest among children whose mothers had the lowest folate levels (<9 ng/mL) during pregnancy (odds ratio [OR], 1.45; 95% confidence interval [CI], 1.13 – 1.87). The authors note that this threshold is above the level currently used to define folate deficiency (<4.4 ng/mL), which is primarily based on the hematological effect of folate. Maternal folate concentrations above the median of 13.6 ng/mL (interquartile range, 9 – 19.6 ng/mL) did not confer additional benefits.

After accounting for covariables, the researchers also found that the combined effect of prepregnancy obesity and low folate level resulted in a threefold increase in the risk for OWO (OR, 3.05; 95% CI, 1.91 – 4.86) when compared with children born to normal-weight mothers with higher folate levels.

Maternal Folate Level More Predictive Than BMI for Childhood Obesity Risk

In addition, when the researchers evaluated data from obese mothers alone, they found that children born to mothers with folate levels of 9 ng/mL or higher had a 43% decrease in their risk for OWO and increased BMI z scores when compared with children born to obese mothers with folate levels below this threshold (OR, 0.57; 95% CI, 0.34 – 0.95; P = .03).
The researchers noted a trend downward in maternal folate levels, depending on BMI, and found that overall, 443 (29.2%) mothers were overweight and 381 (25.1%) mothers were obese in prepregnancy. A total of 590 (38.9%) of the children studied were OWO at ages 2 to 9 years.

“Our findings lend further support that maternal prenatal nutritional status may play an important role in child metabolic disorders,” write Dr Wang and colleagues, and they “underscore the need to establish optimal rather than merely minimal folate concentrations for preventing adverse metabolic outcomes in offspring.”

Two Weight-Loss Drugs Have Highest Odds for 5% Reduction


All five drugs approved by the US Food and Drug Administration (FDA) for long-term use in obese or overweight people were associated with a 5% reduction in weight at 1 year vs placebo, but two — controlled-release phentermine and topiramate (Qsymia, Vivus) and liraglutide (Saxenda, Novo Nordisk) — had the highest odds of hitting that mark, according to a new meta-analysis, published in the June 14 issue of theJournal of the American Medical Association. The five drugs are approved for use in obesity (body mass index [BMI] of at least 30 kg/m2) or in overweight people (BMI of at least 27 kg/m2) who have at least one weight-related comorbidity (type 2 diabetes, hypertension, hyperlipidemia).

Rohan Khera, MD, from the department of internal medicine, University of Iowa Carver College of Medicine, Iowa City, and colleagues analyzed 28 randomized clinical trials that included 29,018 patients (median age, 46 years; 74% women; median baseline weight, 100.5 kg [221.6 lbs]; median baseline BMI, 36.1).

Among the placebo group, 23% achieved 5% weight loss.

Drugs’ Performance

Study drug Participants showing at least 5% weight loss (%) Average weight loss at 1 year (lbs) Odds ratio of 5% loss at 1 year*
Phentermine-topiramate 75 19.4 9.22
Liraglutide 63 11.7 5.54
Naltrexone-bupropion 55 11 3.96
Lorcaserin 49 7.1 3.1
Orlistat 44 5.7 2.7
*Compared with placebo

Most Bang for the Buck for Qsymia?

The systematic review suggests phentermine-topiramate has several advantages for losing weight.

However, coauthor Siddharth Singh, MD, of the School of Medicine at University of California, San Diego, told Medscape Medical News there are several factors beyond the amount of weight loss obtained that patients and physicians should consider.

He said about phentermine-topiramate, “Overall…I think that’s where the most bang for your buck is” but noted that weight loss is different for each patient and different drugs may be more effective or desirable for different patients.

For instance, liraglutide, which is also a medicine for type 2 diabetes and has glucose-lowering effects, may be a more appropriate choice for people who have diabetes, Dr Singh explained.

However, liraglutide is delivered by subcutaneous injection for weight loss, and that may push some people toward a different drug, he added.

And naltrexone-bupropion (Contrave, Orexigen Therapeutics) may be associated with neuropsychiatric properties, such as a potential increased risk of suicide, which must be considered when choosing an agent for certain patients, particularly those with chronic alcohol or drug dependence.

How to Choose
“The approach as to whether to use a particular medication has to be more nuanced,” Dr Singh said. “This just gives an idea of what the magnitude of weight loss across all these medications is.”
Cost is also a consideration. Orlistat, for instance, costs less than the others, but it was associated with the lowest amount of weight loss. Orlistat is available as an over-the-counter medication (Alli, GlaxoSmithKline); it was initially approved as a prescription medicine (Xenical, Roche).

The main outcome evaluated was 5% weight loss, but researchers also looked at 10% weight loss at 1 year.

The ranking among the drugs in terms of estimated percentage of participants who achieved 10% weight loss over 1 year was: phentermine-topiramate, 54%; liraglutide, 34%; naltrexone-bupropion, 30%; lorcaserin (Belviq, Arena Pharmaceuticals), 25%; and orlistat, 20%.

Comparison With Placebo on Adverse Events
Phentermine-topiramate was more likely to help people achieve both 5% and 10% weight loss than all the other drugs, and there was no significant difference in odds of discontinuation from adverse events among phentermine-topiramate, liraglutide, and naltrexone-bupropion.

Compared with placebo, all five drugs had 1.3 to 2.95 higher odds of being associated with discontinuation due to adverse events. Compared with placebo, lorcaserin had the lowest odds of being discontinued (OR, 1.34). Liraglutide and naltrexone-bupropion had the highest odds, at 2.95 and 2.64, respectively.

Among study limitations is the fact that four of the five agents were approved by the FDA within the past 3 years and because there is no weight-loss standard for comparing drugs as part of approval, direct-comparison trials are lacking.

That’s why a network meta-analysis was advantageous, Dr Singh said, so they could compare the drugs with each other.

The next step for the researchers is to compare the same drugs in terms of improving cholesterol levels and blood pressure and “all the things that go into cardiovascular risk,” Dr Singh said. They also need to figure out how the drugs fit with other interventions, such as surgery.

They also add a caution about the need for long-term surveillance: “Historically, concerns regarding the long-term safety profile of pharmacotherapy for weight loss have limited their clinical use, particularly among medications with significant adrenergic actions or central appetite-suppressing actions.

“Short-term clinical trials may not provide comprehensive information on the long-term safety of these agents, and prospective postmarketing surveillance studies are warranted,” they conclude.

Boys with cryptorchidism have smaller postpubertal testicular size vs. healthy controls


Boys with congenital cryptorchidism appear to have similar pubertal timing but reduced postpubertal testicular size compared with normally developing boys, suggesting that cryptorchisdism is a sign of poor perinatal testis development, according to recent findings.

In a longitudinal, case-control study, Jorma Toppari, MD, PhD, professor in the department of physiology and pediatrics at the University of Turku in Finland, and colleagues evaluated data from 119 boys from a birth cohort participating in a previous study at Turku University Hospital. The children were born from 1997 to 2002. Fifty-one boys had a history of congenital cryptorchidism, and 65 were healthy controls without cryptorchidism. For each participant with cryptorchidism, up to two controls were matched for date of birth, parity, gestational age, maternal smoking during pregnancy and maternal diabetes status. All boys who participated in the follow-up were evaluated twice per year.

Examinations included recording of height and weight, and measurement of testicular size and testicular volume by both orchidometer and ultrasound. The researchers defined onset of pubertal testicular growth as the age at which the larger testis was 3 mL by orchidometer at two consecutive visits. The researchers used a nonlinear mixed effect model to assess testicular growth over time in all participants.

The researchers found that in the participants with cryptorchidism, the onset of pubertal testicular growth occurred at a mean 11.7 years, and the control group initiated pubertal growth at a mean 11.8 years (P = .56). No difference was seen between the groups in anthropometric measures.

Control participants had a mean modeled pubertal testicular volume of 0.22 mL and postpubertal testicular volume of 10.2 mL, with half of the testicular volume growth reached at 13.4 years.

No differences were seen in the modeled prepubertal testicular volume of the undescended testes of unilaterally cryptorchid participants vs. the testes of controls or of the bilaterally cryptorchid participants and controls. Postpubertally, however, the modeled testicular volumes of undescended tested were smaller than those of controls in both unilaterally cryptorchid participants (P < .001) and bilaterally cryptorchid participants (P = .01). At the height of testicular growth, no differences were seen between the testes of control participants and those of unilaterally or bilaterally cryptorchid participants.

Orchidometer measurements and testicular length measurements by ruler corresponded closely as cutoffs for defining pubertal onset. When testicular length by ruler was 21 to 25 mm, only 9% of the testes were larger than 3 mL by orchidometer. Conversely, when testicular length was 26 to 30 mm by ruler, 83% of the testes were larger than 3 mL by orchidometer.

“Congenital cryptorchidism is associated with reduced postpubertal testicular size when compared to testes of control boys,” the researchers wrote. “This observation is in line with the assumption that cryptorchidism is a sign of poor perinatal development of testis.” – by Jennifer Byrne