Phase I trial of tipifarnib in patients with recurrent malignant glioma taking enzyme-inducing antiepileptic drugs: a North American Brain Tumor Consortium Study.

PURPOSE: To determine the maximum-tolerated dose (MTD), toxicities, and clinical effect of tipifarnib, a farnesyltransferase (FTase) inhibitor, in patients with recurrent malignant glioma taking enzyme-inducing antiepileptic drugs (EIAEDs). This study compares the pharmacokinetics and pharmacodynamics of tipifarnib at MTD in patients on and off EIAEDs. PATIENTS AND METHODS: Recurrent malignant glioma patients were treated with tipifarnib using an interpatient dose-escalation scheme. Pharmacokinetics and pharmacodynamics were assessed. RESULTS: Twenty-three assessable patients taking EIAEDs received tipifarnib in escalating doses from 300 to 700 mg bid for 21 of 28 days. The dose-limiting toxicity was rash, and the MTD was 600 mg bid. There were significant differences in pharmacokinetic parameters at 300 mg bid between patients on and not on EIAEDs. When patients on EIAEDs and not on EIAEDs were treated at MTD (600 and 300 mg bid, respectively), the area under the plasma concentration-time curve (AUC)(0-12 hours) was approximately two-fold lower in patients on EIAEDs. Farnesyltransferase inhibition was noted at all tipifarnib dose levels, as measured in peripheral-blood mononuclear cells (PBMC). CONCLUSION: Toxicities and pharmacokinetics differ significantly when comparing patients on or off EIAEDs. EIAEDs significantly decreased the maximum concentration, AUC(0-12 hours), and predose trough concentrations of tipifarnib. Even in the presence of EIAEDs, the levels of tipifarnib were still sufficient to potently inhibit FTase activity in patient PBMCs. The relevance of these important findings to clinical activity will be determined in ongoing studies with larger numbers of patients.     

Feasibility and acceptability of a motivational interviewing breastfeeding peer support intervention

An uncontrolled study with process evaluation was conducted in three U.K. community maternity sites to establish the feasibility and acceptability of delivering a novel breastfeeding peer‐support intervention informed by motivational interviewing (MI; Mam‐Kind). Peer‐supporters were trained to deliver the Mam‐Kind intervention that provided intensive one‐to‐one peer‐support, including (a) antenatal contact, (b) face‐to‐face contact within 48 hr of birth, (c) proactive (peer‐supporter led) alternate day contact for 2 weeks after birth, and (d) mother‐led contact for a further 6 weeks. Peer‐supporters completed structured diaries and audio‐recorded face‐to‐face sessions with mothers. Semistructured interviews were conducted with a purposive sample of mothers, health professionals, and all peer‐supporters. Interview data were analysed thematically to assess intervention acceptability. Audio‐recorded peer‐support sessions were assessed for intervention fidelity and the use of MI techniques, using the MITI 4.2 tool. Eight peer‐supporters delivered the Mam‐Kind intervention to 70 mothers in three National Health Service maternity services. Qualitative interviews with mothers (n = 28), peer‐supporters (n = 8), and health professionals (n = 12) indicated that the intervention was acceptable, and health professionals felt it could be integrated with existing services. There was high fidelity to intervention content; 93% of intervention objectives were met during sessions. However, peer‐supporters reported difficulties in adapting from an expert‐by‐experience role to a collaborative role. We have established the feasibility and acceptability of providing breastfeeding peer‐support using a MI‐informed approach. Refinement of the intervention is needed to further develop peer‐supporters' skills in providing mother‐centred support. The refined intervention should be tested for effectiveness in a randomised controlled trial.     

Investigating the Effects of a Multinutrient Supplement on Cognition,Mood and Biochemical Markers in Middle-Aged Adults with ‘Optimal’ and ‘Sub-Optimal’ Diets: A Randomized Double Blind Placebo Controlled Trial

Background: Previous randomized controlled trials examining cognitive and mood effects of combination multivitamin supplements in healthy, non-clinical adults have reported mixed results. One purported explanation for this is that the dietary status of participants at the start of supplement interventions may influence the magnitude of the effect of supplementation. Methods: In this study, we evaluated the effect of a multinutrient formula containing B group vitamins, Bacopa monniera and Ginkgo biloba on memory, attention, mood and biochemical markers of nutrient status in middle-aged adults (M = 52.84 years, n = 141) with ‘optimal’ and ‘sub-optimal’ diets over 12 weeks. We hypothesised that active supplementation would differentially improve memory and attention in those with a ‘sub-optimal’ diet. Results: Mixed model, repeated measures analysis revealed that, in comparison to placebo, active treatment was associated with significant increases in B vitamin status (B1, B6, B12). Regarding behavioural outcomes there was no significant benefit to memory (F(1, 113.51) = 0.53, p = 0.470) nor attention (F(1,113.77) = 1.89, p = 0.171) in the whole cohort. Contrary to our hypothesis, there was a significant beneficial effect of supplementation on attentional performance in individuals with an ‘optimal’ diet prior to supplementation (F(1,57.25) = 4.94, p = 0.030). In the absence of a main effect of supplementation across the entire cohort, there were also a number of significant three-way interactions (treatment by time by diet group) detected in secondary outcomes including lower state anxiety and mental fatigue in those with an ‘optimal’ diet. Conclusion: These findings suggest that the cognitive benefit of B vitamin and herbal supplementation may be dependent on diet quality, supporting the concepts of ‘co-nutrient optimisation’ and interdependency of nutrients. This warrants further investigation. This study advocates characterising the diet of participants prior to supplementation as it may influence the effect of a nutraceutical intervention.     

Definition of a saxitoxin (STX) binding code enables discovery and characterization of the anuran saxiphilin family

American bullfrog (Rana castesbeiana) saxiphilin (RcSxph) is a high-affinity “toxin sponge” protein thought to prevent intoxication by saxitoxin (STX), a lethal bis-guanidinium neurotoxin that causes paralytic shellfish poisoning (PSP) by blocking voltage-gated sodium channels (Na_Vs). How specific RcSxph interactions contribute to STX binding has not been defined and whether other organisms have similar proteins is unclear. Here, we use mutagenesis, ligand binding, and structural studies to define the energetic basis of Sxph:STX recognition. The resultant STX “recognition code” enabled engineering of RcSxph to improve its ability to rescue Na_Vs from STX and facilitated discovery of 10 new frog and toad Sxphs. Definition of the STX binding code and Sxph family expansion among diverse anurans separated by ∼140 My of evolution provides a molecular basis for understanding the roles of toxin sponge proteins in toxin resistance and for developing novel proteins to sense or neutralize STX and related PSP toxins.

Saxitoxin (STX), one of the most potent nonpeptidyl neurotoxins, blocks the bioelectrical signals in nerve and muscle required for life by inhibiting select voltage-gated sodium channel (Na_V) isoforms (1–3). Cyanobacteria and dinoflagellate species associated with oceanic red tides produce this bis-guanidinium small molecule and its congeners, whose accumulation in seafood can cause paralytic shellfish poisoning (PSP), a commercial fishing and public health hazard of growing importance due to climate change (1, 3–5). Its lethality has also earned STX the unusual distinction of being the only marine toxin declared a chemical weapon (1, 3). Select vertebrates, particularly frogs, resist STX poisoning (6–9), a property that is thought to rely on the ability of the soluble “toxin sponge” protein saxiphilin (Sxph) to sequester STX (8, 9). Recent structural studies (10) defined the molecular architecture of the American bullfrog [Rana (Lithobates) castesbeiana] Sxph (RcSxph) (8, 11–14) showing that this 91-kDa soluble, transferrin-related protein from frog heart and plasma has a single, high-affinity STX binding site on its C lobe. Remarkably, even though RcSxph and Na_Vs are unrelated, both engage STX through similar types of interactions (10). This structural convergence raises the possibility that determination of the factors that underlie the high-affinity Sxph:STX interaction could provide a generalizable molecular recognition code for STX that would enable the identification or engineering of STX binding sites in natural and designed proteins.To characterize RcSxph:STX interactions in detail, we developed a suite of assays comprising thermofluor (TF) measurements of ligand-induced changes in RcSxph stability, fluorescence polarization (FP) binding to a fluorescein-labeled STX, and isothermal titration calorimetry (ITC). We paired these assays with a scanning mutagenesis strategy (15, 16) to dissect the energetic contributions of RcSxph STX binding pocket residues. These studies show that the core RcSxph STX recognition code comprises two “hot spot” triads. One engages the STX tricyclic bis-guanidinium core through a pair of carboxylate groups and a cation–π interaction (17) in a manner that underscores the convergent STX recognition strategies shared by RcSxph and Na_Vs (17–22). The second triad largely interacts with the C13 carbamate group of STX and is the site of interactions that can enhance STX binding affinity and the ability of RcSxph to act as a “toxin sponge” that can reverse the effects of STX inhibition of Na_Vs (8, 9).Although Sxph-like STX binding activity has been reported in extracts from diverse organisms including arthropods (13), amphibians (11, 13, 23), fish (13), and reptiles (13), the molecular origins of this activity have remained obscure. Definition of the RcSxph STX recognition code enabled identification of 10 new Sxphs from diverse frogs and toads. This substantial enlargement of the Sxph family beyond RcSxph and the previously identified High Himalaya frog (Nanorana parkeri) Sxph (NpSxph) (10) reveals a varied STX binding pocket that surrounds a conserved core of “hot spot” positions. Comparison of the new Sxph family members further identifies dramatic differences in the number of thyroglobulin (Thy1) domains inserted into the modified transferrin fold upon which the Sxph family is built. Biochemical characterization of NpSxph, Oophaga sylvatica Sxph (OsSxph) (24), Mantella aurantiaca Sxph (MaSxph), and Ranitomeya imitator Sxph (RiSxph), together with structural determination of NpSxph, alone and as STX complexes, shows that the different Sxphs share the capacity to form high-affinity STX complexes and that binding site preorganization (10) is a critical factor for tight STX association. Together, these studies establish an STX molecular recognition code that provides a template for understanding how diverse STX binding proteins engage the toxin and its congeners and uncover that Sxph family members are abundantly found in the most varied and widespread group of amphibians, the anurans. This knowledge and suite of diverse Sxphs, conserved among anuran families separated by at least 140 My of evolution (25), provide a starting point for defining the physiological roles of Sxph in toxin resistance (9, 24, 26), should facilitate identification or design of other STX binding proteins, and may enable the development of new biologics to detect or neutralize STX and related PSPs.     

Knowledge of multidrug-resistant tuberculosis amongst Durban University of Technology students in KwaZulu-Natal,South Africa: the need for integrating public health education

BackgroundKwazulu-Natal is the epicenter of South Africa''s Multidrug-resistant Tuberculosis (MDR-TB) burden which represents a growing threat to public health. Knowledge and awareness of MDR-TB are crucial for effective management and University students are an important vehicle for knowledge transfer of public health education.ObjectiveThis study aimed to evaluate the knowledge of MDR TB and risk factors for transmission, prevention, treatment and control of MDR-TB among Durban University of Technology (DUT) students.MethodsThis quantitative cross-sectional study was conducted among 150 randomly sampled undergraduate students from 3 faculties and data was collected using a validated questionnaire.ResultsWhile a majority of participants (70.67%) had previous knowledge on TB, only 30.67% knew of MDR-TB. Only 23.49% of students reported knowledge of preventative measures associated with MDR TB. Women had a lower probability of having knowledge of MDR-TB compared to men (OR=0.45; CI:0.22,0.95; p<0.05) and students from the Accounting and Informatics faculty were less likely to believe that MDR-TB was a life-threatening illness (OR=0.24; CI:0.05,1.44; p<0.05) and showed limited knowledge of MDR-TB transmission.ConclusionThis study showed that students lacked knowledge of MDR-TB with respect to risk factors, treatment and prevention, which necessitates intervention strategies at a tertiary level to educate and inform students about MDR-TB.     

Primary Care Considerations for the Baseball Athlete

Purpose of ReviewTo summarize current guidance and best practices surrounding non-orthopedic medical concerns in baseball.Recent FindingsDiscussion of COVID19-related practice changes pertaining to the prevention and screening of communicable respiratory illness, concussion protocol updates, the enhanced role of a multi-disciplinary team of mental health professionals.SummaryPrevention, appropriate screening, and early identification remain cornerstones of effective primary care both within the general population as well as for the baseball athlete.     

A Comprehensive Review of COVID-19 Virology,Vaccines,Variants,and Therapeutics

Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),the causative pathogen of the coronavirus disease 2019(COVID-19),has caused more than 179 million in...