Participants had a median age of 80.7 years, with an interquartile range of 73.8 to 86.2 years, and 61.4% were female. From 2010 through 2022, the researchers measured quarterly prescribing rates for typical opioids, tramadol and buprenorphine, together with the gabapentinoids gabapentin and pregabalin. Using an interrupted time-series design, the researchers estimated whether the level and slope of prescribing changed after the CDC released its guideline in March 2016.

Level estimates represented immediate changes in quarterly prescribing rates, while slope estimates captured changes in those rates over time. As an observational analysis, the study assessed an association with the guideline release rather than establishing that the guideline caused the observed prescribing patterns. The results therefore do not support causal attribution of the measured changes to the guideline itself.

Typical opioid prescribing declined by 26.5% over the full study period, but the model did not identify that decline as guideline-related. The estimated change in quarterly trend was 0.09 percentage points, with a 95% confidence interval of −0.1 to 0.3 percentage points, while the estimated immediate level change was −1.5 percentage points, with a 95% confidence interval of −4.1 to 1.0 percentage points. The study thus distinguished the overall decline observed from 2010 to 2022 from the changes statistically associated with the intervention period.

Tramadol showed a different post-guideline pattern. Guideline release was associated with a 27.1% decrease in tramadol prescribing, expressed in the model as an immediate level change of −1.8 percentage points and a trend change of −0.2 percentage points per quarter. Both estimates had 95% confidence intervals that excluded zero: −3.1 to −0.6 percentage points for the level change and −0.3 to −0.1 percentage points for the trend change.

These findings support a selective association between the guideline period and lower tramadol prescribing, rather than a general reduction across opioid categories. Gabapentinoid prescribing, meanwhile, increased from 9.5% to 11.5% during the study period, with no modeled change in trend after the guideline release. The estimated trend change was 0.0 percentage points per quarter, with a 95% confidence interval of −0.01 to 0.02 percentage points.

Buprenorphine prescribing remained near zero throughout. Because the study measured medication use rather than pain relief, adverse effects or symptom control, it could not determine whether the observed analgesic shifts benefited patients or reduced medication-related harm. The population also has heightened exposure to the competing concerns identified in the study’s rationale: the risk of pain undertreatment and the risk of adverse medication effects.

However, the research did not directly compare those outcomes, and its scope was limited to community-dwelling older adults with dementia represented in a national survey. The findings therefore offer no direct evidence about pain treatment or safety outcomes. The authors concluded that the results show analgesic selection shifts after the guideline release, that the clinical impact of those shifts remains unknown, and that more nuanced, evidence-based analgesic prescribing guidance is needed for older adults with dementia.

Subject of Research: Changes in opioid and gabapentinoid prescribing among community-dwelling older adults with dementia after the 2016 CDC opioid prescribing guideline

Article Title: Opioid and Gabapentinoid Prescribing in Older Adults with Dementia Before and After the 2016 CDC Opioid Prescribing Guideline

Article References: Veschio, T., McKendrick, K., Li, L., Harrison, K., Hunt, L. J., Muench, U., Smith, C. B., Aldridge, M., Sean Morrison, R., & Rodin, R. (2026). Opioid and Gabapentinoid Prescribing in Older Adults with Dementia Before and After the 2016 CDC Opioid Prescribing Guideline. Journal of General Internal Medicine. https://doi.org/10.1007/s11606-026-10932-3

Image Credits: AI Generated

DOI: 10.1007/s11606-026-10932-3

Keywords: dementia, opioid prescribing, CDC guideline, gabapentinoids, tramadol, older adults, Medicare claims, interrupted time series, pain treatment, Opioid, Gabapentinoid, Prescribing

The study, conducted at the Quzhou Affiliated Hospital of Wenzhou Medical University in China, included consecutive patients admitted between September 2016 and September 2022. Eligible patients had confirmed acute ischemic stroke, admission and symptom onset within 24 hours, diffusion-weighted magnetic resonance imaging showing an acute infarct within 48 hours, blood samples for C-reactive protein and albumin collected within 48 hours, and complete records needed for analysis. Of 2,150 patients screened, 215 unique patients were removed for incomplete records, missing laboratory data or loss to follow-up, and 169 more were excluded because of hemorrhagic transformation, pre-existing pneumonia, active malignancy, or severe hepatic or renal dysfunction.

Certified neurologists who were blinded to laboratory results assessed early neurological deterioration using the National Institutes of Health Stroke Scale, or NIHSS. Baseline scores were obtained within 24 hours of admission and follow-up scores during the first 72 hours. Patients whose motor-item or total score increased by at least two points were classified as having the outcome. The researchers also recorded age, sex, smoking, hypertension, diabetes, atrial fibrillation, chronic obstructive pulmonary disease, stroke severity, dysphagia, consciousness, blood counts, glucose, kidney function and other laboratory measures. Because the distribution of the C-reactive protein-to-albumin ratio was skewed, values were transformed using a base-2 logarithm before the main analyses.

Patients who deteriorated were older on average than those who did not, with mean ages of 72.3 and 68.7 years, respectively, and atrial fibrillation was more frequent in the deterioration group, affecting 26.3% compared with 14.8%. Median C-reactive protein-to-albumin ratio was 0.12 in the deterioration group, with an interquartile range of 0.05–0.44, compared with 0.07, with an interquartile range of 0.03–0.16, among patients without deterioration. The inflammation marker C-reactive protein and white blood cell count were also higher in the deterioration group, while mean albumin concentration was lower. These differences describe the groups at baseline and do not by themselves establish that the ratio caused neurological worsening.

The pattern was evident when the cohort was divided into quartiles of the log-transformed ratio. Early deterioration occurred in 50 of 508 patients, or 9.84%, in the lowest quartile; 44 of 396, or 11.11%, in the second; 74 of 431, or 17.17%, in the third; and 102 of 431, or 23.67%, in the highest. Patients in the highest quartile had 2.90 times the unadjusted odds of deterioration compared with those in the lowest. After adjustment for age and sex, the odds ratio was 2.66, and the fully adjusted estimate was 1.95 with a 95% confidence interval of 1.27–2.88. A significant trend across quartiles remained in the adjusted analysis.

The fully adjusted model accounted for age, sex, smoking, hypertension, diabetes, atrial fibrillation, chronic obstructive pulmonary disease, baseline NIHSS score, dysphagia, Glasgow Coma Scale score, white blood cell count, fasting plasma glucose and estimated glomerular filtration rate. When the logarithm of the ratio was analyzed continuously, each one-unit increase was associated with an adjusted odds ratio of 1.12 for deterioration, with a 95% confidence interval of 1.03–1.21. Variance inflation factors for the model variables ranged from 1.05 to 2.69, indicating no substantial multicollinearity under the investigators’ criteria. Subgroup estimates were generally positive, but several confidence intervals included no association, and no interaction test was significant; the results therefore did not show that the relationship differed across the examined clinical strata.

As a stand-alone classifier, the ratio showed only modest discrimination for early deterioration, with an area under the receiver operating characteristic curve, or AUC, of 0.627. It performed significantly better than the Age-Atrial fibrillation-Dysphagia-Sex-Stroke severity score, known as A2DS2, whose AUC was 0.520. However, its performance was not significantly different from that of C-reactive protein alone, which had an AUC of 0.624; the comparison between them gave a p-value of 0.111. The ratio also did not differ significantly from neutrophil count, with an AUC of 0.616, or white blood cell count, with an AUC of 0.606.

Adding the ratio to A2DS2 raised the AUC from 0.520 to 0.591, a difference of 0.071 that was statistically significant according to the study’s analysis. Smaller increases were seen when it was added to models containing white blood cell count or neutrophil count. In contrast, adding it to C-reactive protein increased the AUC from 0.624 to only 0.626, and that change was not statistically significant. The findings therefore support the ratio as a potentially inexpensive adjunct derived from routine blood tests, particularly alongside clinical risk assessment, but not as a replacement for C-reactive protein or as a marker with demonstrated superior predictive performance.

Generalized additive and two-piecewise regression models were used to explore whether the relationship changed at a particular value. The models suggested a possible change in slope near a log-transformed ratio of −5.64, corresponding to a raw ratio of approximately 0.020. Below that candidate value, the adjusted odds ratio was 2.35, with a 95% confidence interval of 0.99–5.58; at or above it, the odds ratio was 1.15, with a confidence interval of 1.05–1.26. However, the difference between the two slopes was not statistically significant, and the threshold model did not significantly improve fit over a linear model in a likelihood-ratio comparison. The value of approximately 0.020 is therefore hypothesis-generating rather than a validated biological or clinical cutoff.

Several limitations constrain how the results should be interpreted. The retrospective, single-center design cannot establish causation and may limit generalizability. C-reactive protein and albumin were measured only once within 48 hours, so the analysis could not capture changes in inflammation or nutritional status over time, and residual confounding remains possible despite extensive adjustment. The NIHSS-based definition may not capture every aspect of neurological decline. Patient-level overlap with earlier cohorts from the institutional registry was not quantified, long-term outcomes were not evaluated, and prospective multicenter validation is still required. The findings identify an association between a readily available blood-test ratio and early deterioration after acute ischemic stroke, but they do not show that lowering inflammation or increasing albumin would prevent deterioration, nor do they establish a value at which monitoring or treatment should change.

Subject of Research: Association between the C-reactive protein-to-albumin ratio and early neurological deterioration in acute ischemic stroke

Article Title: Elevated C-reactive protein-to-albumin ratio is associated with early neurological deterioration in acute ischemic stroke: a retrospective cohort study

Article References: Zhou, Z., Xu, W., Wu, Z., Duan, T., Yang, M., Xu, Y., & Ye, J. (2026). Elevated C-reactive protein-to-albumin ratio is associated with early neurological deterioration in acute ischemic stroke: a retrospective cohort study. Frontiers in Neurology, 17, Article 1880425. https://doi.org/10.3389/fneur.2026.1880425

Image Credits: AI Generated

DOI: 10.3389/fneur.2026.1880425

Keywords: acute ischemic stroke, early neurological deterioration, C-reactive protein, albumin, inflammation, blood biomarkers, retrospective cohort, risk prediction, NIHSS, stroke outcome, Elevated, C-reactive

The study, published in BMC Pharmacology and Toxicology, used several complementary measurements to characterize how the combination affected the cancer cells. In addition to the MTT viability assay, the researchers used Annexin V and propidium iodide staining to detect apoptosis, examined cell-cycle distribution and employed quantitative real-time PCR to assess expression of genes associated with apoptosis, resistance to apoptosis and inflammation. An oxidative-stress assay measured glutathione levels. OEC normal epithelial cells served as controls for the in vitro experiments.

Among the clearest findings was that ivermectin attenuated cisplatin-induced S-phase arrest in HN9 cells. Cisplatin alone increased the proportion of cells associated with S-phase arrest, while the combination reduced that response compared with cisplatin monotherapy. The combination was also associated with lower expression of the pro-apoptotic markers BAX and caspase-3 than cisplatin alone. These measured changes were consistent with the lower cytotoxicity observed in the viability assay. Together, the results show that ivermectin interfered with several cellular responses associated with cisplatin in this experimental model, rather than strengthening them.

The treatments also produced differential changes in two measures connected with inflammation and oxidative stress. Expression of tumor necrosis factor alpha, or TNF-α, and cellular glutathione levels varied across the single-drug and combination conditions. The researchers suggested that ivermectin’s antioxidant and anti-inflammatory properties may contribute to its antagonistic interaction with cisplatin. That proposed explanation was not isolated by the experiments, and the results do not establish which molecular process produced the antagonism. The study instead links the reduced cytotoxicity with attenuated S-phase arrest and diminished expression of pro-apoptotic markers while leaving the full mechanism unresolved.

These findings are limited to an in vitro study of one oral cancer cell line, with normal epithelial cells included as controls. The research does not demonstrate a clinical treatment effect, and it does not show how ivermectin and cisplatin would interact in patients. The authors stated that further investigations are needed to clarify the underlying molecular mechanisms and determine whether similar effects occur in other oral cancer models or in vivo settings. Within the tested HN9 cells, however, the evidence demonstrates that ivermectin reduced rather than amplified the cytotoxic, pro-apoptotic and cell-cycle-arresting effects associated with cisplatin.

Subject of Research: Antagonistic interaction between ivermectin and cisplatin in HN9 oral squamous cell carcinoma cells.

Article Title: When drug repurposing backfires: antagonistic effects of ivermectin on cisplatin therapy in oral cancer

Article References: Tantawy, R., Raafat, S. N., El-Gawish, A., & Ghalwash, D. (2026). When drug repurposing backfires: antagonistic effects of ivermectin on cisplatin therapy in oral cancer. BMC Pharmacology and Toxicology. https://doi.org/10.1186/s40360-026-01198-w

Image Credits: AI Generated

DOI: 10.1186/s40360-026-01198-w

Keywords: ivermectin, cisplatin, oral cancer, drug repurposing, drug antagonism, cell viability, apoptosis, cell-cycle arrest, oxidative stress, cancer cell lines, drug, repurposing

The boy was previously healthy and had no prior thyroid disease, neck surgery or recurrent infections. Before admission, he had experienced six days of high fever, reaching 39°C, with pain radiating from his throat to the left ear. Odynophagia began on the second day, followed by hoarseness, neck stiffness and pain during neck movement. He had no stridor, drooling, respiratory distress or clinical features of hyperthyroidism. On admission, his temperature was 38.7°C, heart rate was 117 beats per minute, blood pressure was 113/73 mmHg, respiratory rate was 24 breaths per minute and oxygen saturation was 99% on room air. Examination found pharyngeal erythema, deviation of the uvula to the right, mild thyroid tenderness and painful restriction of neck movement, but no visible swelling, fluctuance or clinical thyrotoxicosis.

Laboratory findings indicated acute inflammation and biochemical thyroid dysfunction. The white blood cell count was 10.8 × 10⁹/L with neutrophil predominance, C-reactive protein was 15.67 mg/dL against a reference range of 0.10–0.50 mg/dL, and procalcitonin was 0.24 ng/mL against a reference range of 0.02–0.10 ng/mL. Thyroid-stimulating hormone was suppressed at 0.02 µIU/mL, while free T3 was elevated at 7.48 pg/mL and free T4 at 2.74 ng/dL. The authors interpreted this pattern as acute, destructive thyroid injury associated with acute suppurative thyroiditis rather than excessive autonomous hormone production. Blood cultures produced no growth after five days, and a respiratory viral polymerase chain reaction test was negative, leaving no identified pathogen in the case.

Imaging demonstrated the infection’s extensive anatomical reach. A lateral neck radiograph showed widening of the prevertebral soft tissue. Contrast-enhanced CT identified a 1.3 × 1.6 × 2.9 cm rim-enhancing collection within an enlarged left thyroid lobe, with extension into the visceral, prethyroid and retropharyngeal spaces. A contiguous 0.7 × 1.3 × 1.5 cm collection was also present in the left parapharyngeal region. The collection produced mass effect on the airway, but there was no mediastinal extension or vascular thrombosis. Flexible laryngoscopy during the acute episode showed a patent airway, normally mobile vocal cords and no pooling of secretions. It also failed to demonstrate a pyriform sinus fistula, a congenital tract that can connect the oropharynx with the thyroid and is often sought in children with left-sided infections.

After discussion between the pediatric and otorhinolaryngology teams, the child was treated conservatively with intravenous ceftriaxone and clindamycin. The authors said surgery was not pursued because the airway remained open, the patient was not systemically toxic, and serial monitoring showed clinical improvement. The team planned to intervene for airway compromise, clinical deterioration, failure of inflammatory markers to improve within 48–72 hours, abscess enlargement on repeat imaging or systemic toxicity. The child became afebrile by day two and resumed eating and drinking. By day three, C-reactive protein had fallen to 3.84 mg/dL and procalcitonin to 0.06 ng/mL, supporting the decision to continue non-operative care rather than proceed with drainage.

An ultrasound-guided aspiration was attempted on day four in an effort to obtain material for cytological and microbiological analysis. The lesion appeared heterogeneous and predominantly hypoechoic with internal echoes rather than a discrete, anechoic fluid collection. Real-time imaging showed the needle tip within the target throughout the procedure, but no material could be aspirated. The authors therefore considered that the inflammatory collection had limited liquefaction. With subacute thyroiditis and an evolving inflammatory phlegmon remaining in the differential, the diagnosis continued to rest on the clinical presentation and imaging rather than a specimen-based microbiological result. A follow-up ultrasound on day five measured the left thyroid collection at 1.0 × 1.2 × 3.0 cm. Because CT and ultrasound used different modalities and imaging planes, the investigators interpreted the comparison as showing no convincing progression rather than a measurable reduction.

By day seven, the C-reactive protein concentration had normalized at 0.54 mg/dL, and the boy was discharged after receiving seven days of intravenous ceftriaxone and clindamycin. He then completed three weeks of oral cefixime and clindamycin, producing a total antibiotic course of four weeks. The oral combination was chosen to retain coverage for streptococcal, staphylococcal and anaerobic organisms while allowing treatment to finish outside the hospital. The course was completed without reported adverse effects or tolerability problems. The boy’s biochemical thyrotoxicosis remained asymptomatic, so no antithyroid treatment was given. His thyroid function had returned to normal at reassessment about 14 months later, with TSH at 2.32 µIU/mL, free T3 at 3.44 pg/mL and free T4 at 0.98 ng/dL. A barium swallow at that visit showed no radiological evidence of a pyriform sinus fistula.

The report distinguishes the infection’s transient thyroid effects from conventional hyperthyroidism. In acute suppurative thyroiditis, inflammation can injure thyroid follicles and release stored thyroid hormone into the circulation, producing suppressed TSH and elevated free T3 and T4 without increased hormone synthesis. The authors state that thionamides, which reduce hormone synthesis, are therefore generally not useful for this destructive process; management is supportive and includes thyroid-function monitoring. In this case, the boy had no symptoms of thyrotoxicosis and received no antithyroid therapy. However, thyroid function was measured at admission and only again about 14 months later, with no intermediate values. The precise time course of recovery could not be established, and an intervening hypothyroid phase could not be excluded.

Several limitations constrain what this case can establish. No causative organism was identified because the aspiration yielded nothing and blood cultures were sterile, and the initial distinction between an abscess and an evolving inflammatory phlegmon therefore rested partly on imaging and clinical assessment. The family missed early follow-up appointments, and no outpatient ultrasound was performed, so the timing of sonographic resolution remains unknown. Although the child was well and had normalized thyroid function without recurrence at the delayed visit, a single negative laryngoscopic examination or barium swallow cannot definitively exclude an intermittently patent or collapsed pyriform sinus fistula. The findings also cannot be generalized to children with airway compromise, systemic toxicity, mediastinal involvement or other warning signs. The report’s practical message is that airway status, systemic condition and treatment response may matter more than the apparent extent of infection alone when deciding whether drainage is necessary, but the authors explicitly describe this observation as hypothesis-generating.

Subject of Research: Pediatric case report of non-operative management of a multispace thyroid abscess with transient thyrotoxicosis.

Article Title: Case Report: Conservative management of pediatric thyroid abscess with multispatial extension and transient thyrotoxicosis

Article References: Almutairi, A. K. (2026). Case Report: Conservative management of pediatric thyroid abscess with multispatial extension and transient thyrotoxicosis. Frontiers in Pediatrics, 14, Article 1951613. https://doi.org/10.3389/fped.2026.1951613

Image Credits: AI Generated

DOI: 10.3389/fped.2026.1951613

Keywords: pediatric thyroid abscess, acute suppurative thyroiditis, conservative management, deep neck infection, transient thyrotoxicosis, antibiotic therapy, pyriform sinus fistula, ultrasound-guided aspiration, case report, Case, Report, Conservative

The researchers enrolled pregnant women at 36 weeks of gestation or later between March 21 and June 20, 2024. Two centers in Bahrain’s Southern Governorate delivered the intervention, while two in the Northern Governorate provided standard care. Of 193 women approached, 175 enrolled, comprising 81 in the intervention arm and 94 in controls. Each intervention package had three inseparable elements: a standardized session delivered by a trained mother-and-child health midwife during a routine antenatal visit, an early booking for a postnatal consultation between six weeks and six months after delivery, and QR-coded educational material. Control centers offered the national program’s usual verbal notification, with women expected to arrange their own postnatal visit after childbirth.

Within the intervention group, immediate changes were striking. Mean knowledge scores on a nine-item scale rose from 2.16 before the session to 8.48 afterward, a mean increase of 6.32 points (95% CI 5.62–7.03; p<0.001). Attitudes measured on an eight-item, 40-point scale increased from 25.79 to 35.89, a mean gain of 10.10 points (95% CI 8.77–11.43; p<0.001). The standardized effect sizes were large, with Cohen’s dz values of 1.98 for knowledge and 1.65 for attitude. Forty-eight percent of intervention participants scored at least 38 out of 40 after the session, and 31 reached the maximum. These measurements were taken minutes apart, however, and the control group was assessed only once. Without a concurrent second measurement, the increases could reflect immediate recall, repeated questionnaire exposure, social-desirability effects or the antenatal visit itself rather than the session alone.

Postnatal attendance was the outcome assessed identically in both arms, using electronic mother-and-child health records at each woman’s own center. A documented consultation with either a physician or a staff nurse counted as attendance. Six of the 175 participants could not be matched to a delivery record, leaving 169 outcomes; the result remained statistically significant under all four extreme assumptions about those missing observations. The observed difference was 31.4 percentage points (95% CI 17.3–45.6), corresponding to a risk ratio of 1.76 and a number needed to treat of about three women for one additional postnatal consultation. Both groups exceeded the 29% national attendance rate recorded in 2019, before face-to-face postnatal services were disrupted by the COVID-19 pandemic. The control proportion also exceeded the 27% found in a 2023 national survey, making it an imperfect estimate of attendance under untreated routine care.

Center-level results expose the study’s central weakness. Attendance was 69.7% and 75.0% in the two intervention centers, but 26.5% and 58.1% in the control centers. The 31.6-percentage-point gap between control centers was as large as the overall difference between study arms, and one control center performed almost as well as the intervention centers. The centers were selected by convenience, their division into study arms was not random, and the arms were geographically separated, making study group completely confounded with governorate. Historical service data were unavailable to establish baseline equivalence. An intraclass correlation coefficient of 0.091 for attendance produced a design effect of 4.73 and an effective sample of approximately 36 women rather than 169. When this clustering adjustment was applied, the confidence interval for the unadjusted odds ratio included the null value.

The adjusted logistic regression strengthened the reported association, with intervention-group status remaining the only significant predictor of attendance. Baseline knowledge and attitude did not independently predict attendance in the model or in exploratory comparisons. That absence of evidence does not establish that understanding and attitudes are unimportant, particularly because the study was not designed to prove an absence of effect. It instead suggests that the structural elements of care may have been more closely connected with attendance than individual scores measured after the session. The intervention cannot identify which component mattered because education, QR-coded material and advance booking were always delivered together. The design also did not measure session duration, training duration, delivery fidelity, staff workload or implementation cost.

The study population offers additional context. Participants were Bahraini women or non-Bahraini women married to Bahrainis, were at least 18 years old, attended antenatal care at 36 weeks or later, spoke Arabic or English, used smartphones and did not have diabetes, hypertension, sickle cell disease or difficulty understanding the educational material. Excluding women without smartphones improved comparability between arms but limited generalizability, since those women may face some of the greatest barriers to postnatal care. The intervention group was older and had a more favorable family-income distribution, while baseline knowledge was also higher and attitudes were less favorable. The study did not establish baseline equivalence between the four centers, and the sample fell short of its target of 100 women per group. Among exploratory medical comparisons, daily medication use was associated with lower attendance, 34.2% compared with 61.8% among women not taking medication, but the finding came from multiple uncorrected subgroup tests and requires dedicated study.

Awareness of the postnatal clinic largely depended on informal networks. Among respondents who knew the clinic existed, 20% cited friends and 18% cited family, making social connections the leading reported sources of information. Doctors during antenatal visits accounted for 17%, doctors after delivery for 16%, and formal health-education sessions for only 3%. These findings connect the intervention to a practical problem: accurate information was often available through relatives and peers, while structured channels were rarely used. The intervention also tested more than information alone. By securing an appointment before delivery, it attempted to remove an organizational step that women in the control arm had to complete independently after childbirth, a task that a prior national survey found many women did not know how to perform.

For practice, the findings support further testing of routine early booking and provider-led counseling as an integrated antenatal service, rather than treating education and appointment logistics as separate issues. Bahrain’s postnatal clinics provide a free consultation for a general maternal assessment, depression screening and counseling on breastfeeding and family planning. The package tested in this study was delivered within an existing antenatal appointment, but the research did not demonstrate its cost, sustainability or acceptability. Confirmation now requires a larger cluster-randomized trial or a stronger quasi-experimental design involving more centers, preferably one capable of separating midwife counseling from advance booking and QR-coded information. Until then, the scientifically supported conclusion is that the combined approach was associated with higher documented postnatal attendance in the participating centers, while knowledge and attitudes improved immediately within the intervention arm. The striking between-arm result warrants attention, but the equally striking center-to-center variation prevents a definitive claim that the package itself caused the increase.

Subject of Research: Antenatal counseling and early postnatal booking in Bahraini primary health care centers

Article Title: Antenatal health education with early postnatal booking and postnatal clinic attendance in primary health care centers in Bahrain: a quasi-experimental study

Article References: Alhaddad, M. E. E., Hubail, M. A. H., Rashed, M. M. A., Alnajjar, I. B. S., Husain, T. K. S., AlAali, F. A., Asoomi, H. A., Makarem, B., Chlif, S., Habbash, F., Almarabheh, A., Salah, A. B., & Shehata, M. H. (2026). Antenatal health education with early postnatal booking and postnatal clinic attendance in primary health care centers in Bahrain: a quasi-experimental study. Frontiers in Public Health, 14, Article 1938634. https://doi.org/10.3389/fpubh.2026.1938634

Image Credits: AI Generated

DOI: 10.3389/fpubh.2026.1938634

Keywords: Bahrain, postnatal care, antenatal education, early booking, maternal health, primary health care, clinic attendance, quasi-experimental study, health services, Antenatal, health, education

Paravertebral tuberculous abscesses are collections associated with spinal tuberculosis that can extend along muscle planes and neurovascular pathways. An enlarging abscess may cause pain, a palpable mass, spinal cord compression or neurological deficits. In the study population, all patients had lumbar spinal tuberculosis with a paravertebral abscess at least 3 cm in transverse diameter and had microbiological confirmation of Mycobacterium tuberculosis through a positive Xpert result, with 12 patients also having positive cultures. The researchers compared outcomes from conventional ultrasound-guided drainage, used for 39 patients between January 2010 and March 2019, with CEUS-assisted drainage, used for 28 patients between August 2018 and January 2025.

CEUS involves administering an intravenous ultrasound contrast agent and observing how contrast enters and washes out of a target region. In this study, 2.4 mL of SonoVue was injected through an antecubital vein, followed by a 5 mL saline flush. The team observed contrast inflow and washout in the target cavity for two minutes and used the recording to guide target selection. This approach was intended to show the vascularity of the abscess wall, the vessels along the planned catheter route, and the distribution of liquefied, necrotic or vascularized components and internal septa. After this assessment, catheter placement followed the same ultrasound-guided technique used in the conventional group.

Both groups received an 8F multifunctional drainage catheter, and the teams followed the same catheter-removal criteria: drainage below 50 mL per day for three consecutive days, predominantly clear fluid and no obvious residual pus on ultrasonography. Bilateral psoas abscesses were drained on both sides. Drained material was collected for smear microscopy, mycobacterial culture and Xpert testing, and all patients continued antituberculosis treatment. The procedures were conducted by members of the same interventional ultrasound team using a standardized technique, although operator experience increased over the 15-year study period. The 67 patients underwent 72 drainage procedures in total, and 53 subsequently underwent definitive surgery.

The principal safety difference was the number of recorded bleeding events. Under the study definition, bleeding included blood-stained drainage fluid, active bleeding at the catheter site after removal, or intra-abdominal bleeding identified through imaging or clinical findings. Five of the 41 conventional procedures met this definition. Four involved blood-stained drainage that resolved within one hour with observation, while one approximately 50-mL catheter-site bleed stopped after one hour of local compression. No bleeding event was recorded in the 31 CEUS-assisted procedures. The Fisher exact test produced a P value of 0.066, so the study did not classify the difference as statistically significant.

Most other drainage-related complications were similar between the groups, both in frequency and in the number of affected procedures. Catheter occlusion occurred in five conventional procedures, or 12.20%, and three CEUS-assisted procedures, or 9.68%. Drain-site pain was recorded in two conventional procedures and one CEUS-assisted procedure. Catheter dislodgement occurred twice after conventional drainage and once after CEUS-assisted drainage, while pericatheter purulent discharge was recorded in three and one procedures, respectively. Other events, including intra-abdominal infection, lumbar artery injury, difficulty removing the catheter and suture entrapment, were uncommon. Two catheters in the CEUS group deformed because of positional compression, and repositioning restored drainage in these cases.

Among the 53 patients who underwent definitive surgery, 30 in the conventional group and 23 in the CEUS group, the investigators found no significant between-group differences in operative time, intraoperative blood loss or length of hospital stay. Mean operative blood loss was 483 ± 126 mL in the conventional group and 457 ± 97 mL in the CEUS group. Mean surgical duration was 206 ± 58 minutes versus 183 ± 70 minutes, and mean hospitalization was 21.5 ± 3.2 days versus 20.1 ± 2.6 days. In the surgery subgroup, 28 of 30 patients in the conventional group and 22 of 23 in the CEUS group met the study’s definition of cure. Recurrence was recorded in two and one patients, respectively, and complication rates in the surgical subgroup did not differ significantly.

Markers of inflammation and pain also improved in both groups at one month, without significant differences between them. In patients who underwent surgery, mean erythrocyte sedimentation rate declined from 45.36 ± 10.35 mm/h before treatment to 26.23 ± 11.76 mm/h at one month in the conventional group and from 44.21 ± 11.39 to 27.50 ± 8.23 mm/h in the CEUS group. Mean C-reactive protein levels fell from 46.67 ± 28.36 to 19.03 ± 9.03 mg/L and from 41.14 ± 24.81 to 18.50 ± 6.12 mg/L, respectively. Mean visual analogue pain scores decreased from 6.62 to 1.95 in the conventional group and from 6.54 to 2.18 in the CEUS group. The analysis was descriptive for these pretreatment and one-month values, and no paired change analysis was performed.

Mean catheter dwell time was shorter in the CEUS group, at 9.7 ± 3.7 days, than in the conventional group, at 11.0 ± 2.4 days, although the study did not report a statistical comparison of these values. The authors proposed that CEUS visualization of liquefied or necrotic compartments, vascularized tissue and internal septa may have helped clinicians select a larger, more drainable target and may partly explain the shorter dwell time. They also noted that catheter position affects evacuation: placement within a well-liquefied compartment can improve drainage, whereas thick material, necrotic debris and granulation tissue can obstruct the catheter. In this cohort, viscous material impeded aspiration in two patients, and two patients developed sinus tracts after repeated puncture, illustrating the potential limitations of needle aspiration when pus is thick or contains tissue and bone fragments.

Several limitations constrain interpretation of the comparison. CEUS was introduced during the later part of the study period, so changes in operator experience, equipment, catheter care and clinical management could not be separated from the imaging strategy. Historical records did not consistently document abscess volume, loculation, vertebral involvement, bone destruction, comorbidities or complete coagulation data, limiting adjusted analysis. Follow-up intervals were not uniform, and cure and recurrence were assessed only in the 53 patients who underwent definitive surgery. The sample was also small, no a priori sample-size calculation was performed, and only five bleeding events were recorded. Patient discomfort, nursing workload and catheter-related costs were not measured. The evidence therefore supports a narrower conclusion: in this retrospective cohort, CEUS-assisted drainage supplied additional anatomical information for catheter planning and was associated with fewer recorded bleeding events, but it did not produce statistically significant differences in most measured outcomes.

Subject of Research: Retrospective comparison of CEUS-assisted and conventional ultrasound-guided catheter drainage for paravertebral tuberculous abscesses

Article Title: Contrast-enhanced ultrasound-assisted catheter drainage for paravertebral tuberculous abscesses: a retrospective study of procedural safety

Article References: Li, D., Chen, P., & Zhang, W. (2026). Contrast-enhanced ultrasound-assisted catheter drainage for paravertebral tuberculous abscesses: a retrospective study of procedural safety. Frontiers in Medicine, 13, Article 1970327. https://doi.org/10.3389/fmed.2026.1970327

Image Credits: AI Generated

DOI: 10.3389/fmed.2026.1970327

Keywords: contrast-enhanced ultrasound, catheter drainage, paravertebral abscess, spinal tuberculosis, ultrasound guidance, procedural safety, bleeding complications, retrospective cohort, Contrast-enhanced, ultrasound-assisted, catheter, drainage

Patient-specific quality assurance, or PSQA, checks whether the dose delivered during radiotherapy agrees with the approved treatment plan. EPID-based methods are attractive because the imaging panel is integrated into the accelerator and can acquire a two-dimensional record of the beam actually emerging from the treatment head. Such images can be compared with calculated portal-dose images and evaluated with gamma analysis, producing both a summary pass rate and a spatial display of discrepancies. The drawback is that conventional EPID PSQA is generally performed once, before treatment begins, so its result describes the machine’s condition on that particular day rather than its condition for every subsequent fraction.

The study addressed that limitation by training a Pix2Pix conditional generative adversarial network to translate an Anisotropic Analytical Algorithm portal-dose calculation into a predicted EPID image. The authors tested two output designs: one that predicted the full EPID intensity and another that predicted the dose-difference map between calculated and measured images. They also compared three input and training configurations: a baseline using only the calculated image, a model conditioned on daily Machine Performance Check data, and a third model that added synthetic multi-leaf collimator deviations to its training set. These axes produced six model variants, all built with the same U-Net-style generator and trained for 2,000 epochs.

The machine-state input consisted of 235 features selected from 253 values recorded by the Halcyon system’s automated daily quality-assurance procedure. Most were related to the positions and backlash of the 57 leaves in each bank of the dual-layer multi-leaf collimator. Seven additional values described beam output, uniformity, field edges, collimator rotation and EPID calibration. Each deviation was normalized by its own quality-control tolerance, allowing features expressed in millimetres, percentages and degrees to enter the network on comparable scales. The vector was projected into a 4096-dimensional embedding, reshaped into a feature map and stacked with the calculated portal-dose image before processing by the U-Net generator.

The dataset comprised 135 normally delivered arc fields from 50 patients treated between April 2023 and October 2024. The patients included eight head-and-neck cases, 34 pelvic cases, of which 26 were prostate treatments, six thorax cases and two extremity cases. All plans used two or three arcs and the 6 MV flattening-filter-free beam. Patient-level separation kept all arcs from a patient in the same subset: 107 fields from 39 patients were used for training and 28 fields from 11 patients formed the common test set. Images were resampled to a uniform 256-by-256 matrix at 1 mm spacing, with no rotation, translation or cropping augmentation.

Because clinically delivered plans rarely contain large collimator errors, the researchers also created 36 deliberately perturbed fields. They selected six base arcs and applied six preset plus-or-minus 1 mm positioning patterns, including asymmetric single-bank shifts, symmetric aperture widening or narrowing, and localized changes affecting selected leaves. The modified plans were physically re-delivered and measured on the accelerator. Corresponding leaf positions in the machine-performance vectors were adjusted by the same offsets, producing paired examples in which the recorded machine state and measured image changed consistently. Twenty-six perturbed fields were added to training, while 10 were combined with their six unperturbed source arcs in a separate plan-paired evaluation set.

On the common 28-field test set, the full difference-target model achieved the best overall agreement with measured gamma passing rates. At 3%/2 mm, its root-mean-square error was 0.48 percentage points and its correlation was 0.944, compared with errors of 0.69 and 0.55 percentage points for the baseline difference-target and EPID-target models. At the stricter 2%/2 mm criterion, the full difference-target model recorded an error of 1.27 percentage points and a correlation of 0.936, while the corresponding baseline errors were 2.01 and 1.68 percentage points. However, bootstrap confidence intervals for the differences between the full and baseline difference-target models included zero, and an exact paired Wilcoxon test found no significant difference in per-field absolute errors on normal plans. The authors therefore characterized the numerical advantage on unperturbed cases as part of the sampling variability rather than confirmed superiority.

The clearest effect appeared in the deliberately perturbed fields. At 3%/2 mm, mean absolute gamma-passing-rate error in the difference-target chain fell from 3.67 percentage points in the baseline model to 2.94 points after adding machine-performance conditioning, then to 2.12 points after also adding deviation-aware augmentation. The full 42% reduction was statistically significant for the paired perturbed samples, with p equal to 0.020. The corresponding reduction in the EPID-target chain was smaller, from 3.45 to 2.71 percentage points, and adding machine-state information alone reversed the direction of that chain’s prediction error. Feature-masking experiments showed why: replacing the 228 MLC-related values with their nominal state increased the full model’s signed error on perturbed plans from positive 1.83 to positive 3.40 percentage points, while masking non-MLC groups had little effect.

Pixel-level detection remained substantially weaker than plan-level prediction. Across all model variants, sensitivity to gamma failures ranged from 19.65% to 32.18%, depending on the criterion and configuration, meaning that most failing pixels were not identified. Specificity and accuracy were high, reaching as much as 99.88% and 99.67%, respectively, but the researchers cautioned that a predicted gamma passing rate cannot replace physical measurement or reliably localize every failure region. The study was also restricted to one institution and one Halcyon v3.0 platform, its perturbation set contained only 1 mm collimator-position offsets, and the plan-paired test set was small. The results therefore establish retrospective agreement and perturbation sensitivity, not clinical readiness, and the authors call for prospective testing of error detection, false-negative risk and stability across treatment fractions.

Subject of Research: Deep learning for machine-state-aware prediction of radiotherapy delivery quality using EPID-based patient-specific quality assurance

Article Title: A deep learning approach for EPID-based patient-specific quality assurance incorporating daily machine-state variations

Article References: Pak, K., Kim, S.-W., Park, K., Cho, B., Kim, Y. J., Song, S. Y., Jeong, C., & Kwak, J. (2026). A deep learning approach for EPID-based patient-specific quality assurance incorporating daily machine-state variations. Frontiers in Oncology, 16, Article 1911466. https://doi.org/10.3389/fonc.2026.1911466

Image Credits: AI Generated

DOI: 10.3389/fonc.2026.1911466

Keywords: radiotherapy, patient-specific quality assurance, electronic portal imaging, deep learning, gamma passing rate, linear accelerator, multi-leaf collimator, generative adversarial network, machine performance check, deep, learning, approach

The study included 3,971,083 reported cases and 661 deaths across all 31 provincial-level administrative regions. Investigators used Joinpoint regression to assess long-term trends, time-series decomposition to quantify seasonality, and global Moran’s I and Local Indicators of Spatial Association, or LISA, to assess spatial autocorrelation and local clusters. They also evaluated six forecasting models for each province: a neural network, exponential smoothing with state-space models, seasonal autoregressive integrated moving-average models, a hybrid model, a Bayesian structural time-series model and Prophet. Model performance was compared through a composite standardised index.

Incidence declined throughout the study period, and the estimated rate of decline accelerated after 2017. Joinpoint analysis estimated an annual percentage change of minus 11.47 for 2004–2017 and minus 18.85 for 2017–2020. The timing of seasonal peaks remained relatively stable from year to year, although the amplitude of those peaks decreased. These results distinguish a continuing reduction in the overall burden from a largely unchanged annual seasonal pattern.

Spatial clustering was statistically significant during 2004–2019 and weakened to its lowest level in 2020, although the significance of the 2020 result depended on the spatial-weight specification used. Beijing and Tianjin had the highest incidence of bacillary dysentery, while southwestern provinces had a higher burden of amoebic dysentery. The analysis also found that children aged zero to one year accounted for the largest single-year age-band share, at 13.1% of cases. Because the study used aggregated surveillance data, it could not examine individual exposures or separate the effects of specific interventions, changes in care-seeking and reporting, and other influences on observed incidence.

For the pandemic-period comparison, province-specific forecasting models were trained on data from 2004–2019 and used to generate pre-pandemic baselines for 2020. Observed national incidence was then compared with the combined provincial projections. In six provinces, reported incidence fell below the lower bound of the corresponding 95% prediction interval, indicating that the reduction exceeded the range expected from the pre-existing trend and seasonal models. The overall deviation coincided temporally with COVID-19 control measures, but the observational design supports an association rather than a causal conclusion. The results show that the national decrease in 2020 was accompanied by persistent seasonality, geographic clustering and provincial disparities, with the strongest reductions in some regions and less uniform departures from baseline elsewhere.

Subject of Research: Spatiotemporal surveillance and forecasting of dysentery incidence in mainland China, 2004–2020

Article Title: Dysentery in Mainland China, 2004–2020: spatiotemporal dynamics and changes during the COVID-19 pandemic period

Article References: Ma, H., Ke, D., Xu, M., Zhou, X., Lei, Z., Huang, B., Liu, Q., & Lei, Z. (2026). Dysentery in Mainland China, 2004–2020: spatiotemporal dynamics and changes during the COVID-19 pandemic period. BMC Public Health. https://doi.org/10.1186/s12889-026-29811-x

Image Credits: AI Generated

DOI: 10.1186/s12889-026-29811-x

Keywords: dysentery, China, disease surveillance, COVID-19 measures, time-series forecasting, spatial clustering, seasonality, bacillary dysentery, amoebic dysentery, Mainland, spatiotemporal, dynamics

Researchers used data from the community-based Reference Abilities Neural Network study at Columbia University. The analysis included adults aged 20 to 80 who were recruited mainly through random-market mailing in the greater New York area and were free of cognitive impairment, functional impairment and medical or psychiatric conditions that could affect cognition. Participants had a mean age of 56.6 years, with a standard deviation of 15.6 years; half were women, and 71.4% were white. Of 398 cohort members, 112 had the metabolomic, cognitive and functional magnetic resonance imaging data required for the study. These included participants were older than those excluded and had higher reasoning and language cognitive scores and a higher language neural-network score.

Each participant completed a neuropsychological battery containing three tests in each of four domains: episodic memory, reasoning, processing speed and language. Domain scores were derived with principal-axis factor analysis and standardized across the cohort, so that higher values represented better performance. The researchers also used functional MRI acquired while participants performed 12 in-scanner tasks, three for each domain. Memory tasks included logical memory, word-order recognition and paired associates; fluid reasoning included paper folding, matrix reasoning and letter sets; speed tasks included digit symbol, letter comparison and pattern comparison; and language tasks included synonyms, antonyms and picture naming.

The imaging analysis summarized each domain with a scaled subprofile modeling approach, which derived an activation pattern whose subject-level score best predicted performance in that domain. The resulting four network scores were designed to capture patterns of task-related brain activity associated with memory, reasoning, speed and language. In parallel, plasma samples were analyzed by untargeted liquid chromatography coupled to high-resolution mass spectrometry. Two chromatographic columns and positive or negative ionization produced technical replicates, which were processed for peak detection, alignment and batch correction. A feature was defined by its mass-to-charge ratio and retention time. Of 7,327 features detected with the hydrophilic interaction column and 6,806 detected with the C18 column, 4,286 were present in at least 70% of samples and entered the analysis.

Eight separate metabolome-wide association analyses tested the 4,286 features against four neural-network outcomes and four cognitive outcomes. Models for brain networks adjusted for age and sex, while models for cognitive performance also adjusted for education. Benjamini-Hochberg correction at a false discovery rate of 5% was the primary threshold. The analysis identified no metabolite features associated with any cognitive domain after correction, and none linked to the memory, speed or language network scores. The eight surviving associations all involved reasoning-network activation. Five were tentatively annotated: three as creatinine, one as a sphingomyelin, and one as a feature compatible with several phosphatidylcholines and phosphatidylethanolamines. Three creatinine features were inversely associated with the reasoning-network score, while the sphingomyelin and the multi-identity phospholipid feature had positive associations.

Because so few individual associations survived the primary correction, the researchers also conducted exploratory analyses using nominal p-values below 0.05. These analyses associated 1,199 metabolite features with at least one neural-network domain, including six features associated with all four networks. For cognitive performance, 568 features were associated with at least one domain, but only one feature was associated with all four; it was tentatively identified as a group of methylated inositol isomers that the assay could not distinguish. The broad cross-domain cognitive feature was interpreted cautiously because the analysis did not control the false-positive rate at the individual-feature level. The scale of these nominal findings therefore demonstrates how many statistical associations can appear in a high-dimensional metabolomic screen, rather than providing robust evidence of a biomarker.

Pathway analysis pointed toward several broad metabolic themes, including amino acid metabolism, lipid metabolism, energy production, cofactor and vitamin metabolism and nitrogen handling. After false-discovery-rate correction, arginine and proline metabolism was enriched for the memory network, while de novo fatty-acid biosynthesis and fatty-acid oxidation were enriched for the reasoning network. No cognitive-domain pathway remained significant after correction. In the exploratory pathway analysis, memory had the largest variety of enriched pathways and the greatest overlap between neural-network and cognitive results, including beta-alanine metabolism, butanoate metabolism, lysine metabolism, branched-chain amino-acid degradation and urea-cycle or amino-group metabolism. These pathway results describe statistical enrichment, not demonstrated mechanisms of brain change.

The limited correspondence between metabolites associated with brain-network scores and those associated with test performance was itself a central observation. Under the nominal threshold, the same-domain analyses yielded 12 overlapping features for memory, 22 for reasoning, 43 for processing speed and 73 for language. Even among the six features associated with all four neural networks, only two also met the cognitive threshold for speed and language, while two more were associated exclusively with language. The investigators noted that several possible explanations are plausible: blood oxygenation-dependent functional MRI signals may be more closely coupled to circulating metabolism than behavioral test scores; the in-scanner and outside-scanner tasks were not identical; and different aspects of a cognitive domain can be supported by partially distinct biological processes. The overlap data do not show that cognition and functional imaging are measuring unrelated systems.

The study’s main strengths are its simultaneous use of high-resolution metabolomics, standardized domain scores and domain-specific imaging patterns in cognitively normal adults across a broad age range. Untargeted metabolomics allowed the researchers to screen thousands of molecular features without restricting analysis to a preselected metabolic hypothesis. A sensitivity analysis that treated measurements below the detection limit as missing produced beta estimates correlated with those from the primary analysis at 0.66 to 0.83 across outcomes, indicating that handling low-intensity values did not entirely account for the results. Principal-component analysis also found no small set of components dominating the metabolomic data; the first three explained 13%, 8% and 5% of variance, with a gradual scree-plot decline.

Important limitations constrain the findings. The sample of 112 was small for testing thousands of metabolite features, reducing statistical power and the ability to detect modest associations. The selected sample differed from the wider cohort in age and several cognitive and imaging measures, raising concerns about selection bias and generalizability. Domain-level activation scores compress potentially important regional and subnetwork differences, while 31% of analyzed features could not be mapped to a putative metabolite and many of the remaining annotations were uncertain. Plasma compounds also may not closely represent metabolism within the central nervous system, and the models could not rule out residual confounding from diet, kidney function, medication use and other factors. The cross-sectional design cannot determine whether circulating metabolites precede neural changes, accompany them or reflect them.

Overall, the results offer a qualified picture of domain specificity rather than a set of clinically ready metabolic markers. Robust associations were confined to reasoning-network activation, whereas measured cognitive performance showed no metabolite associations after correction for multiple comparisons. The limited overlap across cognitive domains, neural networks and pathways suggests that blood metabolomic profiles may capture aspects of brain physiology that are more proximal, and more selective, than conventional test scores. At the same time, the small sample, exploratory nominal findings, uncertain metabolite identities and potential confounding mean that the eight surviving feature associations should be treated as hypotheses for replication. The authors call for larger, well-characterized longitudinal cohorts, along with finer analyses of individual functional subnetworks and brain regions, to determine whether these metabolic relationships are reproducible, domain-specific and relevant to neurodegeneration.

Subject of Research: Associations between plasma metabolomic features, domain-specific cognition and neural-network activation in cognitively normal adults

Article Title: Domain-specific associations of metabolomic features with cognition and neural networks among cognitively normal adults

Article References: Vollmer, B. L., Habeck, C., Kalia, V., Vardarajan, B. N., Scarmeas, N., Miller, G. W., Stern, Y., & Gu, Y. (2026). Domain-specific associations of metabolomic features with cognition and neural networks among cognitively normal adults. Frontiers in Neuroscience, 20, Article 1898605. https://doi.org/10.3389/fnins.2026.1898605

Image Credits: AI Generated

DOI: 10.3389/fnins.2026.1898605

Keywords: metabolomics, cognition, functional MRI, neural networks, plasma metabolites, reasoning, brain aging, cognitively normal adults, Domain-specific, associations, metabolomic, features

Theobromine is 3,7-dimethylxanthine, one of the principal naturally occurring methylxanthines alongside caffeine and theophylline. It is a bitter, purine-related alkaloid found principally in the seeds of the cocoa tree, with cocoa beans containing approximately 3.3% the compound. Other dietary sources include kola nut, guarana, tea and yaupon holly. The molecule has a reported elimination half-life of roughly six to eight hours and produces milder central nervous system stimulation than caffeine. Caffeine has an additional methyl group, crosses the blood–brain barrier more efficiently and is generally a stronger stimulant. Theobromine is also formed in the human body during caffeine metabolism, making exposure common rather than strictly dietary.

Parkinson’s disease is a progressive neurodegenerative disorder defined by the loss of dopaminergic neurons in the substantia nigra and the accumulation of aggregated α-synuclein in Lewy bodies. Dopamine degeneration reduces dopamine signaling in basal-ganglia circuits involved in motor control, while non-motor features can include cognitive impairment, depression, sleep disturbance and autonomic dysfunction. The disease is not explained solely by dopamine-cell loss: cellular and animal evidence also implicates lysosomal, endosomal and mitochondrial dysfunction, α-synuclein propagation and immune responses. The clinical phase follows preclinical neurodegeneration and a prodromal period in which subtle or non-motor symptoms may already be present.

The enzyme most directly relevant to dopamine breakdown is monoamine oxidase B, or MAO-B, a flavin adenin dinucleotide-dependent enzyme located on the outer mitochondrial membrane. MAO-B oxidatively deaminates dopamine and other monoamines, generating 3,4-dihydroxyphenylacetaldehyde and an equimolar amount of hydrogen peroxide. The aldehyde can modify proteins and nucleic acids. Hydrogen peroxide can react with ferrous iron in the Fenton reaction to generate hydroxyl radicals, which can damage cellular components. These reactions are especially relevant in an aging Parkinson’s brain, where MAO-B activity and cerebral iron are reported to rise, glutathione-mediated peroxide detoxification may be reduced, and aldehyde dehydrogenase expression in the substantia nigra is diminished.

MAO-A and MAO-B share approximately 70% amino-acid sequence homology and closely similar catalytic pockets, but they differ in substrate preferences and inhibitor selectivity. MAO-A preferentially metabolizes serotonin, norepinephrine, epinephrine and melatonin. MAO-B acts strongly on benzylamine and phenethylamine and is largely expressed in astrocytes and serotonergic neurons; dopamine is a common substrate for both isoforms. Selegiline, rasagiline and safinamide are established MAO-B inhibitors used in Parkinson’s disease treatment. By reducing dopamine breakdown, they can increase dopamine availability and lower levodopa requirements, but no treatment has yet been conclusively demonstrated to halt the underlying neuronal degeneration.

Theobromine may intersect with Parkinson’s biology through several pathways. As a non-selective adenosine-receptor antagonist, it acts on A1, A2A, A2B and A3 receptors, which regulate intracellular cyclic adenosine monophosphate through G proteins. It also competitively inhibits phosphodiesterases that hydrolyze cyclic signaling molecules, potentially increasing cAMP. In a mouse experiment, oral theobromine raised brain levels of phosphorylated vasodilator-stimulated phosphoprotein, phosphorylated cAMP response element-binding protein and brain-derived neurotrophic factor, while the treated animals performed better in a three-lever motor-learning task. These findings concern experimental signaling and behavior in mice, not a clinical effect in people with Parkinson’s disease.

Other animal studies have reported neuroprotective or cognitive effects under conditions that differ from Parkinson’s disease but are relevant to neurodegeneration broadly. In rats subjected to transient global cerebral ischemia and reperfusion, theobromine reduced thiobarbituric acid reactive substances, a marker of lipid peroxidation, and increased glutathione content. In six-month-old rats fed a high-cholesterol diet, administration of 30 mg of theobromine mitigated induced memory and cognitive impairment. In a chronic cerebral hypoperfusion model, theobromine reduced latency to fall in the rotarod test, increased latency in the elevated-plus-maze test and enhanced novel-object recognition memory. Mouse hippocampal recordings further indicated enhanced synaptic transmission alongside reduced magnitude of long-term potentiation; adenosine A1 and A2A receptor antagonists blocked the respective effects.

Caffeine, theobromine’s better-studied chemical relative, has stronger epidemiological and laboratory support in the Parkinson’s field. In the Honolulu Heart Program, 8,004 Japanese-American men were followed for 30 years, and midlife coffee consumption of at least 784 mg per kg per day was associated with an approximately fivefold reduction in the risk of Parkinson’s disease by age 65 compared with non-coffee consumers, after adjustment for age and smoking. Inverse associations also appeared in the Health Professionals’ Follow-Up Study, involving 47,351 men, the Nurses’ Health Study, involving 88,565 women, and other prospective or case-control investigations. Animal models show caffeine protecting dopaminergic neurons against the mitochondrial toxins MPTP, 6-hydroxydopamine and rotenone, as well as reducing pathological changes in an α-synuclein fibril model. These caffeine findings cannot be assumed to apply equally to theobromine.

Structural analysis helps explain why theobromine may still be useful as a research starting point. Its xanthine scaffold carries methyl substituents at positions 3 and 7, and these appear to influence both enzyme inhibition and receptor activity. Position 3 methylation is important for MAO-B inhibition, while position 7 methylation can enhance MAO-B inhibition and A2A-receptor antagonism. Theobromine’s non-competitive inhibition of primary amine oxidase was proposed to involve hydrogen bonding between its nitrogen at position 1 and amino-acid residues in the enzyme, although the enzyme’s ping-pong catalytic mechanism complicates interpretation of this kinetic pattern. Theobromine also inhibits PARP-1, a nuclear enzyme involved in DNA repair and immune regulation, providing another laboratory pathway potentially relevant to inflammatory responses.

The central limitation is the mismatch between laboratory promise and clinical evidence. The reported methylxanthine experiments examined enzyme inhibition in human adipose tissue rather than the brains of people with Parkinson’s disease, and they do not show that theobromine inhibits both dopamine-metabolizing MAO isoforms in patients. There are no reported randomized controlled trials of theobromine for Parkinson’s disease, and it remains unknown whether ordinary dietary intake produces brain concentrations sufficient to alter MAO-B or adenosine signaling meaningfully. Many mechanistic studies use concentrations that may exceed those achieved in vivo. Common MPTP, 6-hydroxydopamine and α-synuclein models reproduce selected aspects of neurodegeneration rather than the full, heterogeneous human disorder.

Human observational evidence for theobromine itself is also limited. A reported positive association between dietary theobromine and cognitive performance in a representative United States population, and a finding linking intake with less cognitive decline among older men, do not establish a causal effect. Another study reported a positive correlation between theobromine intake and depression, highlighting the limits and potentially adverse signals in the available data. Chocolate and cocoa contain numerous bioactive compounds, so associations involving those foods cannot isolate the contribution of theobromine. The current evidence therefore indicates biological plausibility and supports further controlled investigation; it does not show that cocoa provides protection against Parkinson’s disease or that theobromine should be used as a treatment.

Subject of Research: Laboratory evidence on theobromine’s potential neuroprotective and monoamine oxidase effects in Parkinson’s disease

Article Title: Theobromine and Parkinson’s disease

Article References: Kondeva-Burdina, M., Bacheva, E., & Mitkov, J. (2026). Theobromine and Parkinson’s disease. Pharmacia, 73, Article e189281. https://doi.org/10.3897/pharmacia.73.e189281

Image Credits: AI Generated

DOI: 10.3897/pharmacia.73.e189281

Keywords: theobromine, Parkinson’s disease, monoamine oxidase B, dopamine metabolism, adenosine receptors, cacao, neurodegeneration, animal models, clinical evidence, Parkinson, disease, scientific research