Medical Bulletin 23/ September/ 2024 - Video

A recent study, published in BMC public health, has unveiled an association between sedentary lifestyle and coffee consumption. According to the authors, sedentary behavior for more than 6 hours/day along with no coffee consumption is strongly related to increased risk of mortality from all cause and cardiovascular diseases.

Sitting for longer hours is independently linked to harmful health outcomes, including cancerous, metabolic and cardiovascular disease. On the contrary, coffee consumption is believed to have protective effect on all cause and cardiovascular diseases mortality because of its antioxidant qualities.

In the current prospective cohort study, researchers the combined effect of daily sedentary time and coffee consumption on death from all causes and cardiovascular diseases.

Data of 10639 participants was collected from the National Health and Nutrition Examination Surveys conducted from 2007 to 2018. Personal interviews, physical examination and lab tests were conducted for each participant. Global physical activity questionnaire (GPAQ) was used to measure total sitting time per day. On the basis of the questionnaire, 4 groups were divided: 0-4h, 4-6h, 6-8h, more than 8h per day. Based on total reported coffee intake, coffee consumers were divided into no coffee intake, 0.23–326 g/day, 326–540 g/day, and ≥ 540 g/day.

The primary study outcomes were cardiovascular disease and all-cause death, established using ICD-10 numbers. Sociodemographic variables included sex, ethnicity, race, educational attainment, marital status, poverty income ratio, body mass index (BMI), and waist circumference. Lifestyle factors like smoking, alcohol consumption and Healthy eating index 2015 were also assessed. Other relevant factors like hypertension, hypercholesterolemia, cancer diagnosis, history of cardiovascular diseases and diabetes were also noted.

Over a 13-year follow-up, the researchers found, 945 fatalities occurred among research participants, with 284 of these being due to cardiovascular diseases.

The authors concluded that all-cause mortality was reduced in the highest quintile of coffee intake and any amount of coffee intake was linked to decreased risk of cardiovascular disease mortality.

The combined analysis of this study identified that the association of sedentary lifestyle with increased mortality was only observed among adults with no coffee consumption but not among those who had coffee intake.

Reference: Zhou, H., Nie, J., Cao, Y. et al. Association of daily sitting time and coffee consumption with the risk of all-cause and cardiovascular disease mortality among US adults. BMC Public Health 24, 1069 (2024). https://doi.org/10.1186/s12889-024-18515-9

Findings from the international FORT-2 clinical trial showed that a combination treatment including immunotherapy is safe and tolerable in patients with locally advanced or metastatic bladder cancer. The results, which were recently published in JAMA Oncology, show potential to broaden the number of patients with bladder cancer who could benefit from immunotherapy, an approach that harnesses a patient's own immune system to fight cancer.

The tumor microenvironment (TME) plays a critical role in predicting response to immunotherapy. Tumors with a T-cell-inflamed microenvironment—which are characterized by infiltration of CD8+ T cells, chemokines, a group of protein that help in migration of immune cells, and an interferon signature— respond well to immunotherapies and are associated with improved survival. In urothelial bladder cancer, increased T cell infiltration has been correlated with longer patient survival.

“In 2016, we published studies showing that the tumors with FGFR3 mutations have no T cell infiltration, which led to the logical conclusion that blocking the FGFR pathway could make more patients responsive to immunotherapy,” said Sweis.

In pre-clinical cancer models, the combination of FGFR inhibitor and a programmed cell death ligand 1 (PD-L1) inhibitor showed increased survival and antitumor activity, suggesting clinical utility of this combination.

It is the first clinical trial to evaluate the safety, tolerability and the recommended phase 2 dose of FGFR inhibitor plus PD-L1 inhibitor in advanced urothelial cancer patients with FGFR mRNA high expression. The study enrolled and treated 37 patients between May 15, 2018 and July 16, 2021.

“By measuring FGFR mRNA gene expression, we found that half of the patients’ tumors have activation of the FGFR pathway, whereas previous studies reported only about 15% using a method that measured only FGFR DNA mutations, suggesting overexpression of FGFR captures all mutations and additional tumors where this pathway is relevant,” said Sweis.

In previous studies, the response rate reported was 23% with PD-L1 inhibitor, atezolizumab alone and 21% with rogaratinib alone; however, by combining the FGFR inhibitor and PD-L1 inhibitor, the response rate increased to 54%. In addition, the responses were achieved quickly, with a median time to response of 2.1 months, and included many durable responses lasting longer than 2 years.

Despite negative expression for PD-L1 and lack of FGFR3 gene alteration in most patients treated with this combination therapy, the objective response rate in this subgroup was 53%, indicating that positive therapeutic effect was not dependent on PD-L1 expression or FGFR3 gene alteration status.

“The next-generation, more selective FGFR inhibitors are being developed, which should improve tolerability and combining them with PD-L1 inhibitor may yield better results with fewer side effects,” said Sweis.

Reference: Sweis RF, Gajate P, Morales-Barrera R, et al. Rogaratinib Plus Atezolizumab in Cisplatin-Ineligible Patients With FGFR RNA-Overexpressing Urothelial Cancer: The FORT-2 Phase 1b Nonrandomized Clinical Trial. JAMA Oncol. Published online September 19, 2024. doi:10.1001/jamaoncol.2024.3900

A new study from King’s College London published in Nature Medicine reveals A new type of blood test using lipids could make it easier to identify children at risk of complications around obesity including type two diabetes, liver and heart disease.

The findings also contest the common idea that cholesterol is a leading cause of complications around obesity in children, identifying new lipid molecules which contribute to health risks like blood pressure but are not only correlated with a child’s weight.

Lipids have traditionally been thought to be fatty acids in the body, either good or bad types of cholesterol or triglycerides, fats found in the bloodstream that is the most common in the human body. Recent studies from the same group of scientists have suggested that the picture is more complex.

Using a technique associated with chemistry called mass spectrometry, current evidence puts the types of different lipid present in the body in the thousands, each with separate functions.

Taking a control sample of 1,300 children with obesity, the team assessed their lipids in blood. Afterwards 200 of them were put on the HOLBAEK-model for a year, a lifestyle intervention for people with obesity popular in Denmark.

Subsequent readings showed that amongst the intervention group, counts of lipids tied to diabetes risk, insulin resistance and blood pressure decreased, despite limited improvements in some children’s BMI.

Dr Cristina Legido-Quigley, a group leader in Systems Medicine at King’s College London, Head of Systems Medicine at the Steno Diabetes Centre Copenhagen (SDCC) and principal author, said: “For decades, scientists have relied on a classification system for lipids that have split them into good and bad cholesterol, but now with a simple blood test we can assess a much broader range of lipid molecules that could serve as vital early warning signs for illness. In the future, this has the potential to be an entirely new way to evaluate someone’s personal risk of disease and by studying how to change lipid molecules in the body, we could even prevent metabolic diseases like diabetes altogether.”

Dr Karolina Sulek, who was part of the study and performed analysis at the SDCC, said: “Early recognition of children at risk for these life-threatening diseases is crucial. The study provides strong evidence of the great need for obesity management and gives parents confidence to intervene in their children’s life more compassionately, helping them to lose weight."

Reference: Huang, Y., Sulek, K., Stinson, S.E. et al. Lipid profiling identifies modifiable signatures of cardiometabolic risk in children and adolescents with obesity. Nat Med (2024). https://doi.org/10.1038/s41591-024-03279-x

A new study has revealed that the brain undergoes major changes during pregnancy, some fleeting and others more enduring.

Researchers, for the first time, have mapped the changes that unfold as a woman's brain reorganizes in response to pregnancy, based on scans carried out 26 times starting three weeks before conception, through nine months of pregnancy and then two years postpartum.

The study documented a widespread decrease in the volume of cortical gray matter as well as an increase in the microstructural integrity of white matter located deeper in the brain. Both changes coincided with rising levels of the hormones estradiol and progesterone.

The scientists said that since the study's completion they have observed the same pattern in several other pregnant women who have undergone brain scans in an ongoing research initiative called the Maternal Brain Project. They aim to expand the number into the hundreds.

"It's pretty shocking that in 2024 we have hardly any information about what happens in the brain during pregnancy. This paper opens up more questions than it answers, and we are just scratching the surface of these questions," Chrastil added.

The scans showed a reduction averaging about 4% in gray matter in roughly 80% of the brain regions studied. A small rebound postpartum did not return the volume to pre-pregnancy levels. The scans also showed an increase of about 10% in white matter microstructural integrity, a measure of the health and quality of the connections between brain regions, peaking late in the second trimester and early in the third trimester, then returning to pre-pregnancy status postpartum.

"The maternal brain undergoes a choreographed change across gestation, and we are finally able to observe the process in real time," said University of California, Santa Barbara neuroscientist Emily Jacobs, senior author of the study.

The researchers said it is not clear that the loss of gray matter is a bad thing.

"This change could indicate a fine-tuning of brain circuits, not unlike what happens to all young adults as they transition through puberty and their brain becomes more specialized. Some changes we observed could also be a response to the high physiological demands of pregnancy itself, showcasing just how adaptive the brain can be," University of Pennsylvania postdoctoral scholar and study lead author Laura Pritschet said.

Reference: Pritschet, L., Taylor, C.M., Cossio, D. et al. Neuroanatomical changes observed over the course of a human pregnancy. Nat Neurosci (2024). https://doi.org/10.1038/s41593-024-01741-0

UW Medicine researchers found that patients who underwent the stone-moving ultrasound procedure had a 70% lower risk of recurrence. The Journal of Urology published the findings.

“I think the main takeaways of this study are removing fragments reduces relapse and using a noninvasive, hand-held ultrasound device to help clear these kidney stone fragments,” said UW Medicine urologist Dr. Jonathan Harper, the study’s senior author.

The multisite, randomized and controlled trial was conducted from May 2015 to April 2024. Almost all of the 82 participants were from the UW Medicine or the VA Puget Sound health systems. All had stone fragments that had persisted in their kidneys for months, and their ureters were free of stones and fragments.

In the study, 40 underwent ultrasound treatment to encourage fragments to clear from the kidneys, while 42 control-group members received no such treatment.

With patients awake in a clinic office setting, doctors used a wand that generated ultrasonic pulses through the skin to move the fragments closer to the ureter, where they could be naturally expelled, sometimes with the next urination, Harper noted.

Harper and his co-lead author on the paper, urologist Dr. Mathew Sorensen, have worked on this technology and treatment for 15 years. They also use this technology, called burst wave lithotripsy, to blast larger stones into smaller pieces; those successes were published in 2022.

The pushing and breaking technologies are used with the same ultrasound platform.

“I see a lot of potential in this It could become as common as getting your teeth cleaned. If you have a couple of small stones which could cause future problems, you make an office appointment and in 30 minutes you’re done.“This could really revolutionize kidney stone treatment,” Harper said.

Reference: Sorensen MD, Dunmire B, Thiel J, Cunitz BW, Burke BH, Levchak BJ, Popchoi C, Holmes AE, Kucewicz JC, Hall MK, Dighe M, Dai JC, Cormack FC, Liu Z, Bailey MR, Porter MP, Harper JD. Randomized Controlled Trial of Ultrasonic Propulsion-Facilitated Clearance of Residual Kidney Stone Fragments vs Observation. J Urol. 2024 Aug 14:101097JU0000000000004186. doi: 10.1097/JU.0000000000004186. Epub ahead of print. PMID: 39146526.