The influence of the crystal synthesis method on the crystallographic structure of caffeine-citric acid cocrystals was analyzed thanks to the synthesis of a new polymorphic form of the cocrystal. In order to compare the new form to the already known forms, the crystal structure of the new cocrystal (C8H10N4O2·C6H8O7) was solved by powder X-ray diffraction thanks to synchrotron experiments. The structure determination was performed using `GALLOP\', a recently developed hybrid approach based on a local optimization with a particle swarm optimizer, particularly powerful when applied to the structure resolution of materials of pharmaceutical interest, compared to classical Monte-Carlo simulated annealing. The final structure was obtained through Rietveld refinement, and first-principles density functional theory (DFT) calculations were used to locate the H atoms. The symmetry is triclinic with the space group P-1 and contains one molecule of caffeine and one molecule of citric acid per asymmetric unit. The crystallographic structure of this cocrystal involves different hydrogen-bond associations compared to the already known structures. The analysis of these hydrogen bonds indicates that the cocrystal obtained here is less stable than the cocrystals already identified in the literature. This analysis is confirmed by the determination of the melting point of this cocrystal, which is lower than that of the previously known cocrystals.

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BACKGROUND: Study Summary: In today\'s world, caffeine is the most commonly consumed psychostimulant globally. While moderate caffeine intake is generally safe, there have been reported cases of significant toxicity and even fatal outcomes. Although rare, increased awareness and clinical suspicion are crucial in identifying such cases and providing timely life-saving interventions. In this report, we present a case of a 27-year-old female patient who was hospitalized due to severe systemic and cardiac effects resulting from the ingestion of a large quantity of caffeine capsules as a suicide attempt. We provide a detailed account of the clinical presentation and the management of the patient, including the emergency room\'s life-saving interventions and the complex care provided in the intensive care unit until the patient\'s complete recovery. Our aim with this case presentation is to raise awareness about the severe consequences of caffeine intoxication, particularly the cardiac injury, and to highlight the state-of-the-art treatment approaches in addressing this issue.

The bisindolic alkaloid caulerpin (CAU) is a bioactive compound isolated from green algae of the genus Caulerpa that are highly invasive in the Mediterranean Sea. On the other side, the purine alkaloid caffeine (CAF) is one of the most globally consumed psychoactive substances and a widespread anthropogenic water pollutant. Both compounds display a large panel of biological properties and are well known to accumulate in the tissues of aquatic organisms and, in certain circumstances, co-occur in the human diet. On this premise, the present study aimed to investigate possible synergistic interactions between CAU and CAF by using the bivalve Mytilus galloprovincialis as a model organism. Mussels were exposed to CAF via medium while they were fed with food enriched with CAU. After treatments, biochemical analysis confirmed the toxic potential of CAF, with increased AChE activity and lipid peroxidation. Also, histopathological alterations were observed in the gills and digestive tubules. The NMR-based metabolomics analysis detected higher levels of free amino acids under CAF treatments. Conversely, the food administration of CAU did not affect the above toxicological biomarkers. In addition, we did not observe any cumulative effect between CAF and CAU toward increased cellular damage and neurotoxicity. On the other hand, a possible action of CAU in decreasing CAF toxicity could be hypothesized based on our results. This hypothesis is supported by the activity of CAU as an agonist of peroxisome proliferator-activated receptors (PPARs). PPARs mediate xenobiotic detoxification via cytochromes P450, which is involved in CAF metabolism. Overall, the results obtained not only rule out any cumulative adverse effects of CAF and CAU but also encourage further research to evaluate the possible use of CAU, a compound easily obtained through the valorization of biomass from invasive species, as a food additive to improve the clearance of xenobiotics.

OBJECTIVE: Although diet is one of the potential environmental factors affecting ulcerative colitis (UC), evidence is not sufficient to draw definitive conclusions. This Japanese case-control study examined the association between the consumption of coffee, other caffeine-containing beverages and food, and total caffeine and the risk of UC.
METHODS: The study involved 384 UC cases and 665 control subjects. Intake of coffee, decaffeinated coffee, black tea, green tea, oolong tea, carbonated soft drinks, and chocolate snacks was measured with a semiquantitative food-frequency questionnaire. Adjustments were made for sex, age, pack-years of smoking, alcohol consumption, history of appendicitis, family history of UC, education level, body mass index, and intake of vitamin C, retinol, and total energy.
RESULTS: Higher consumption of coffee and carbonated soft drinks was associated with a reduced risk of UC with a significant dose-response relationship (P for trend for coffee and carbonated soft drinks were <0.0001 and 0.01, respectively), whereas higher consumption of chocolate snacks was significantly associated with an increased risk of UC. No association was observed between consumption of decaffeinated coffee, black tea, green tea, or oolong tea and the risk of UC. Total caffeine intake was inversely associated with the risk of UC; the adjusted odds ratio between extreme quartiles was 0.44 (95% confidence interval: 0.29-0.67; P for trend <0.0001).
CONCLUSIONS: We confirmed that intake of coffee and caffeine is also associated with a reduced risk of UC in Japan where people consume relatively low quantities of coffee compared with Western countries.

Comprehensive analysis of multi-omics data can reveal alterations in regulatory pathways induced by cellular exposure to chemicals by characterizing biological processes at the molecular level. Data-driven omics analysis, conducted in a dose-dependent or dynamic manner, can facilitate comprehending toxicity mechanisms. This study introduces a novel multi-omics data analysis designed to concurrently examine dose-dependent and temporal patterns of cellular responses to chemical perturbations. This analysis, encompassing preliminary exploration, pattern deconstruction, and network reconstruction of multi-omics data, provides a comprehensive perspective on the dynamic behaviors of cells exposed to varying levels of chemical stimuli. Importantly, this analysis is adaptable to any number of omics layers, including site-specific phosphoproteomics. We implemented this analysis on multi-omics data obtained from HepG2 cells exposed to a range of caffeine doses over varying durations and identified six response patterns, along with their associated biomolecules and pathways. Our study demonstrates the effectiveness of the proposed multi-omics data analysis in capturing multidimensional patterns of cellular response to chemical perturbation, enhancing understanding of pathway regulation for chemical risk assessment.

Animal husbandry wastewaters represent an important source of pharmaceuticals into the environment. This work aimed to evaluate the occurrence of pharmaceuticals and their hazard in wastewater from a model dairy farm from Costa Rica. Among the seven pharmaceuticals detected (acetaminophen, caffeine, carbamazepine, ibuprofen, ketoprofen, risperidone, sulfamethazine), caffeine, ibuprofen and acetaminophen showed the highest concentrations, while caffeine, carbamazepine and risperidone were the most frequently detected compounds. High (HQ ≥ 1) or medium (0.1 ≤ HQ < 1) hazard were estimated for three (caffeine, ibuprofen, risperidone) and two (acetaminophen, ketoprofen) pharmaceuticals, respectively; similarly, high overall hazard (∑HQ) and significant ecotoxicity were determined in samples from all sampling points. According to our results, the release of these aqueous matrices is a matter of environmental concern, as the treated wastewater is used for farm irrigation or directly released into nearby water streams. This work contributes to the knowledge on the scarcely described occurrence and risk of pharmaceuticals in Latin American regions.

Chronic cluster headache (CCH) is a rare but severely debilitating primary headache condition. A growing amount of evidence suggests that occipital nerve stimulation (ONS) can offer effective treatment in patients with severe CCH for whom conventional medical therapy does not have a sufficient effect. The paresthesia evoked by conventional (tonic) stimulation can be bothersome and may thus limit therapy. Burst ONS produces paresthesia-free stimulation, but the amount of evidence on the efficacy of burst ONS as a treatment for intractable CCH is scarce.
In this case series, we report 15 patients with CCH treated with ONS at Aarhus University Hospital, Denmark, from 2013 to 2020. Nine of these received burst stimulation either as primary treatment or as a supplement to tonic stimulation. The results were assessed in terms of the frequency of headache attacks per week and their intensity on the Numeric Rating Scale, as well as the Patient Global Impression of Change (PGIC) with ONS treatment.
At a median (range) follow-up of 38 (16-96) months, 12 of the 15 patients (80%) reported a reduction in attack frequency of ≥50% (a reduction from a median of 35 to 1 attack/week, p < 0.001). Seven of these patients were treated with burst ONS. A significant reduction was also seen in maximum pain intensity. Overall, 10 patients stated a clinically important improvement in their headache condition following ONS treatment, rated on the PGIC scale. A total of 16 adverse events (nine of which were in the same patient) were registered.
Occipital nerve stimulation significantly reduced the number of weekly headache attacks and their intensity. Burst ONS seems to function well alone or as a supplement to conventional tonic ONS as a preventive treatment for CCH; however, larger prospective studies are needed to determine whether the effect can be confirmed and whether the efficacy of the two stimulation paradigms is even.

In this paper, the determination of both oxidizable and reducible compounds within a single chromatographic run is exploited for the first time, using a low-pressure chromatographic system and multiple pulse amperometric detection. The case study selected focussed on the analysis of green coffee extracts. The separation of the compounds was carried out using a 1-cm length monolithic column and an eluent prepared by mixing an aqueous solution of an ion-pair reagent, perfluoroheptanoic acid (PFHpA), and acetonitrile. The parallel determination of oxidizable and reducible compounds was performed by application of two consecutive pulses, E1 = +1.6 V and E2 = -1.5 V. At anodic conditions, the chromatographic peaks for 5-caffeoylquinic acid (5-CQA), caffeine and 5-feruloylquinic acid (5-FQA) were detected, while at cathodic conditions, a chromatographic peak was ascribed for trigonelline. In the developed methodology, the use of multiple pulse amperometry provided better sensitivity if compared to previously described amperometric methodologies determining either oxidizable or reducible compounds. Detection limits for the referred compounds of ca. 1 × 10-5 mol L-1, an analysis rate of 12 h-1 and an acetonitrile consumption of 0.07 mL per analysis were achieved. The approach presented demonstrates the possibility of combining low pressure chromatographic systems and multiple pulse amperometry, in the development of new, low-cost and fast methodologies for multi-analyte determinations.

The most common congenital anomaly is orofacial cleft, which is categorized into two main types: cleft lip with or without cleft palate (CL/P) and cleft palate only (CPO). One of the most accepted etiologies is multifactorial (gene-environment). This study aimed to identify the amendable risk factors of an orofacial cleft in Northern Thailand. A retrospective case-control study in Maharaj Nakorn Chiang Mai Hospital was conducted from 2011 to 2020. One hundred and seventeen cases of CL/P and CPO were included. Forty-nine normal children were enrolled in a time-matched control group. Exploratory survey data on maternal exposures were collected. Multivariate logistic regression was used to estimate the adjusted association between maternal exposures and CL/P, and CPO occurrence. Multivariate analysis identified three predisposing factors that increased the risk of CL/P and CPO. The first factor was caffeine consumption with a total amount of 560 mg/week (adjusted OR: 7.59; 95% CI: 2.48-23.23; p < 0.001). The second factor was any smoker or passive smoking (adjusted OR: 8.47; 95% CI: 1.63-43.92; p = 0.011). The third factor was a low socioeconomic status (income of lower than 270 USD/month; adjusted OR: 4.05; 95% CI: 1.07-15.27; p = 0.039). From the 10-year study in Northern Thailand: caffeine consumption, exposure to cigarette smoke, and low socioeconomic status were identified as associated negative factors for orofacial clefts. We propose that preconceptional counseling for risk reduction should be emphasized in reducing the mother\'s exposure to these factors. Future investigations in large multicenter populations are suggested.