Dasyrhynchus giganteus plerocercoids encysting in the musculature of Indian halibut (Psettodes erumei): seasonal prevalence, morpho-molecular characterization, and histopathological alterations.

This study investigated the prevalence, morphology, molecular identification, and histopathological effects of larval tapeworms (plerocercoids) infecting the skeletal muscles of the Indian halibut (Psettodes erumei) collected from the coastal waters of the Arabian Gulf. Numerous oval or round blastocysts, measuring 13-26 mm, were found embedded within the muscular tissues of the Indian halibut, rendering the fish unsuitable for human consumption. Morphological and molecular analyses identified the plerocercoids as Dasyrhynchus giganteus (family Dasyrhynchidae), with an overall prevalence of 15.4%. The seasonal prevalence was the highest in summer (14.6%), followed by spring (10.6%), winter (4.4%), and autumn (3.5%). Infection rates increased with fish size. Histopathological examination revealed fibrous connective tissue capsules surrounding the larvae, causing muscular atrophy and degenerative changes, with few inflammatory eosinophilic cells. Molecular and phylogenetic analysis of the 28S rDNA gene sequences confirmed the specimens as D. giganteus, clustered closely with other sequences of D. giganteus with 100% bootstrap values. This study provided valuable insights into the parasitic infection dynamics, seasonal variation, molecular identification, and histopathological effects, highlighting the importance of monitoring fish for food safety and public health implications.

Evaluating the Efficacy of Methocarbamol and Nefopam in Orthopedic Surgical Pain.

Introduction Pain after orthopedic surgeries represents a special concern in patients with fractures. The use of multimodal analgesia significantly reduced the opioid need and reduced the risk of their side effects. Objectives This study compared the effectiveness and safety of methocarbamol and nefopam in the reduction of post-operative pain for patients undergoing orthopedic surgeries. Method This prospective, double-blind, randomized controlled trial took place at Al-Sader Teaching Hospital in Basrah, Iraq, from the first of February 2022 to the end of October 2023. The study aimed to assess the post-operative pain relief efficacy and safety of intramuscular nefopam (20 mg) and intravenous methocarbamol (1 g) in 110 adults (aged 18-65) undergoing elective orthopedic surgeries. Exclusions were made for allergies to the drugs, substance abuse history, and severe hepatic or renal impairment. Participants were randomized into two groups, with pain intensity measured at one hour, six hours, and 12 hours post-operation using the visual analog scale (VAS). Side effects were also evaluated. Statistical analysis was done using SPSS 27, with a significance level set at p<0.05 and a 95% confidence interval (CI). Results  In this study, we conducted a rigorous comparison between two groups, methocarbamol and nefopam, to evaluate their efficacy and safety in post-operative pain management. We started by ensuring that the groups were well-matched in terms of age, gender distribution, and body mass index (BMI). The results showed remarkable similarities in mean age, gender distribution, and BMI, supported by robust p-values, affirming the effective matching of the two groups. Moving to pain management, we observed a significant advantage in favor of methocarbamol. At all-time intervals (one hour, six hours, and 12 hours post-operation), methocarbamol consistently demonstrated lower mean VAS scores compared to nefopam. These differences were highly statistically significant, underscoring the superior pain relief efficacy of methocarbamol. Exploring side effects, we found no statistically significant disparities in the occurrence of nausea and vomiting between the two groups. However, there was a noticeable trend toward higher tachycardia incidence in the nefopam group, though it did not reach statistical significance. Conclusion The present study showed a higher efficacy of methocarbamol in post-operative pain reduction in comparison to nefopam. No serious side effects were observed with both drugs.

First report of Kudoa species (Myxozoa, Multivalvulida) infection in purple-spotted Bigeye (Priacanthus tayenus) from the Saudi Arabian Gulf.

The purple-spotted bigeye, Priacanthus tayenus, is a marine benthic fish native to the Indian and Pacific Oceans, including the Arabian Gulf in Saudi Arabia. This study identified a myxozoan parasite infecting wild P. tayenus from the Saudi Arabian Gulf. These parasites produced spherical to ovoid-shaped, white plasmodia enclosed within pseudocysts in the fish musculature. The annual infection rate was 5.1%, with the highest prevalence in summer (7.6%), followed by spring (6%), and autumn (2.5%), while no infections were observed in winter. The number of plasmodia per fish ranged from 100 to 150 (135.1 ± 16.2). Their dimensions were 4-4.7 mm (4.3 ± 0.3 mm) in length and 4.5-7 mm (6 ± 1.1 mm) in width. Milky-colored exudates within the plasmodia contained mature spores measuring 8-9 µm (8.6 ± 0.4 µm) x 6-7.5 µm (6.9 ± 0.5 µm). The polar capsules of the spores exhibited dimensions of 2-5 µm (3.5 ± 0.5 µm) x 2.5-4.5 µm (3 ± 0.45 µm). Both morphological and genetic analyses confirmed these plasmodia as a novel Kudoa species. Histopathological examination revealed atrophy in the surrounding muscles without an inflammatory response. This study documents the first occurrence of a novel Kudoa sp. in P. tayenus at the Jubail landing site in Saudi Arabia, emphasizing the need for further surveillance and investigations to elucidate its pathogenesis and implications for wild fish stocks.

Desmoid Tumor of the Rectus Abdominis with Urinary Bladder Involvement: A Case Report and Review of Literature.

Desmoid tumors (DTs) account for 3% of all soft tissue tumors. They are benign and have no malignant potential with a favorable prognosis, and predominantly occur in young women. The pathogenesis and clinical behavior of DTs are still uncertain. In addition, most cases of DTs were associated with abdominal trauma (including surgery), while genitourinary involvement seemed to be quite rare. Up to now, there has been only one DT case with urinary bladder involvement reported in the literature. We, Hereby, report a 67-year-old male patient with left lower abdominal pain while micturition. Computed tomography (CT) showed a mass located at the lower aspect of the left rectus muscle with an extension attached to the urinary bladder. Based on the pathological findings of tumor specimen, a diagnosis of benign desmoid tumor (DT) of the abdominal wall was made. Laparotomy with wide local excision was carried out. The patient had a smooth postoperative recovery and was discharged after 10 days. Introduction:Historically, MacFarland first described these tumors in 1832. Etymologically, the word desmoid was first coined by Muller in 1838 and is derived from the Greek word desmos, which means band or tendon-like. Stout first used the term fibromatosis in 1961[1,2,3]. Desmoid tumors (DTs) are a kind of rare neoplasm, which represents 3% of all soft tissue tumors and 0.03% of all neoplasms with an incidence of 5 to 6 per million of the population per annum[4,5,6]. DTs predominantly affect young females with a median age of 30 to 40 years old and is more than twice in female than male patients. However, there is no gender preference in older patients [7,8]. Furthermore, the symptoms of DTs are not typical in general. Symptoms can occasionally occur due to the size and location of the tumor but usually are nonspecific. Because of its rarity and unusual behavior, DT is often associated with diagnostic and therapeutic challenges. Computed tomography (CT) and magnetic resonance imaging (MRI) is beneficial for the diagnosis of this tumor but pathological diagnosis is mandatory. Surgical resection is now considered as the most efficient treatment option for patients with DT, because it offers a good chance of long-term survival. Our case is of unusual presentation and finding of abdominal wall desmoid tumor with an extension to urinary bladder in a male patient who is 67 years old. Keywords: desmoid tumor, fibromatosis, spindle cell tumor, urinary bladder.

Huffmanela selachii n. sp. (Nematoda: Trichosomoididae: Huffmanelinae): A new species infecting the skin of the great hammerhead shark (Sphyrna mokarran) and the blacktip reef shark (Carcharhinus melanopterus) in the Arabian Gulf, off-shore Saudi Arabia.

From January 2017 - December 2019, 75 out of 850 (8.8 %) great hammerhead sharks from the Arabian Gulf had skin lesions of black irregular discolorations on the ventral surface of the head. The lesions consisted of pencil-like lineations often advancing forward by about 2 mm in back-and-forth looped scribbles often forming a relatively linear bands of about 5-7 cm wide. Similar lesions were also found in the blacktip reef shark from the same area within the same period, and consisted of straight to irregular black lines, extended indiscriminately across the skin of the sharks. Microscopic examination of the skin revealed the presence of dark-brown eggs exhibiting the spindle or ellipsoidal eggs characteristic of Huffmanela sp. The morphometrics of eggs from both hosts were similar (62.9-89.9 µm long and 29.3-56.1 µm wide). The eggshells were smooth with polar plugs protruding or not, with an abruptly truncated crown-like or shoulder-like collar surrounding the plug. The eggs were only found in the epidermal layer of the skin. Based on the unique morphometrics of the eggs, we report a new species, named: Huffmanela selachii n. sp.. This appears to be the first report of Huffmanela from either the great hammerhead shark or the blacktip reef shark, and the third reported Huffmanela in sharks from the Arabian Gulf. It is also one of few species reported from connecting waters of the greater Indian Ocean. This new finding contributes to our understanding of the diversity and ubiquity of Huffmanela sp. in marine creatures.

Morphomolecular identification and considerations of the infestation site adaptations of Pricea multae (Thoracocotylidae: Priceinae) from Scomberomorus commerson, off Arabian Gulf, Saudi Arabia.

Monogeneans Pricea multae naturally infested 42 of the 120 (35%) mackerel fish (Scomberomorus commerson) examined. For the first time, an infestation was discovered off the coast of Jubil in the Arabian Gulf of Saudi Arabia. Based on the structure clarified through light and electron microscopy of mounted specimens and molecular analysis of rDNA and measurements of this monogenean parasite was identified as P. multae. The tegumental surface of the parasite was characterized by tegumental ridges running transversally, generating folds in both the dorsal and ventral surfaces of the body at regular intervals. The study clarified the importance and function of the micro-structures, such as tegumental folds, perforations, sensory ganglia present on the parasite's surface, and the larger hamulus supported by a relatively unmodified internal spine. This monogenean parasite has adapted to its host infestation site uniquely.

Mycobacterium avium subsp. paratuberculosis and microbiome profile of patients in a referral gastrointestinal diseases centre in the Sudan.

Mycobacterium avium subsp. paratuberculosis (MAP) causes Johne's disease in animals with zoonotic potential; it has been linked to many chronic diseases in humans, especially gastrointestinal diseases (GID). MAP has been extensively studied in Europe and America, but little reports were published from Africa. Sudan is a unique country with close contact between humans and livestock. Despite such interaction, the one health concept is neglected in dealing with cases of humans with GID. In this study, patients admitted to the reference GID hospital in the Sudan over a period of 8 months were screened for presence of MAP in their faeces or colonic biopsies. A total of 86 patients were recruited for this study, but only 67 were screened for MAP, as 19 did not provide the necessary samples for analysis. Both real-time PCR and culture were used to detect MAP in the collected samples and the microbial diversity in patients´ faecal samples was investigated using 16S rDNA nanopore sequencing. In total, 27 (40.3%) patients were MAP positive: they were 15 males and 12 females, of ages between 21 and 80 years. Logistic regression analysis revealed no statistical significance for all tested variables in MAP positive patients (occupation, gender, contact with animal, milk consumption, chronic disease, etc.). A unique microbiome profile of MAP-positive patients in comparison to MAP-negative was found. These findings suggest that a considerable proportion of the population could be MAP infected or carriers. Therefore, increase awareness at community level is urgently needed to decrease the risk of MAP at human/animal interface. This study represents the first report of MAP in humans in the Sudan; nevertheless, a better view of the situation of MAP in humans in the country requires a larger study including patients with other conditions.

An evaluation of a novel nanoformulation of imatinib mesylate in a mouse model of lupus nephritis.

Studies have suggested imatinib mesylate (ImM) as a potential treatment for systemic lupus erythematosus nephritis (SLEN). However, ImM has limited renal excretion. The goal of the current research was to develop an ImM containing nanoformulation, conduct studies to evaluate pharmacokinetics, and determine whether kidney deposition can be enhanced in a mouse model of SLEN. A fish oil-based ImM oil-in-water nanoemulsion was developed and characterized for particle size, zeta potential, pH, and stability. MRL/MpJ-Faslrp (model of SLEN) and MRL/MpJ (control) mice (12-13 weeks) received one dose of ImM as either a nanoemulsion or naked drug. Pharmacokinetics and kidney deposition studies were performed. Statistics were conducted with a student's T-test. The nanoemulsion characteristics included particle size range of 60-80 nm, zeta potential of -6.6 to -7.8 mV, polydispersity index < 0.3, 3-day stability at 4 °C, and limited ImM leakage from the nanoemulsion in serum. Pharmacokinetics of the nanoformulation showed changes to pharmacokinetic parameters suggesting reduced systemic exposures (with reduced potential for toxicities) to ImM. Kidney deposition of ImM was threefold higher after 4 h in the MRL/MpJ-Faslrp mice that received the nanoformulation vs. naked drug. The current study showed encouraging results for development of a stable and well-characterized nanoemulsion for optimizing kidney deposition of ImM. Future strategies will define dose-efficacy and dose-toxicity relationships and evaluate approaches to further enhance kidney delivery and optimize deposition to the mesangial location of the kidney.

Morphological and pathological appraisal of Huffmanela sp. (Nematoda: Trichosomoididae) infecting orange-spotted grouper (Epinephelus coioides, Hamilton, 1822) at Jubail Province, Saudi Arabia: a case report.

This paper is conducted for identifying the parasite which collected during regular routine inspection for the hygienic condition and health status of fish in 2019 at the central fish market shops at Jubail city, Saudi Arabia. Samples from an orange spotted grouper (Epinephelus coioides) fish showed heavy black streaks between the muscle fibers that was considered unmarketable and rejected by the consumer after had been cut and prepared for sealing. The black discolorations were in the form of heavy diffused focal black spots or forming threads of variable sizes embedded in the entire whole-body musculature of the fish. These samples were subjected to parasitological and pathological evaluation. The parasitological examination of the affected muscular tissues revealed infection by Huffmanela spp. eggs. The parasitic infection was identified on the bases of the morphological and ultra-structural characters of the eggs. The examination of the affected fish showed multifocal black parasitic remnants between the muscle fibers. The parasitic fragments were distributed all over the fish flesh either superficially in subcutaneous area or deep inside the muscular tissue and they have been concentrated in the flesh around the vertebral column. In conclusion; this case report confirmed the occurrence of Huffmanela spp. infection in the muscles of Epinephelus coioides by using light and scanning electron microscopy. Further molecular assessment is recommended.

Tenofovir-diphosphate in peripheral blood mononuclear cells during low, medium and high adherence to emtricitabine/ tenofovir alafenamide vs. emtricitabine/ tenofovir disoproxil fumarate.

OBJECTIVE: Tenofovir alafenamide (TAF) preferentially loads peripheral blood mononuclear cells (PBMCs), resulting in higher PBMC tenofovir-diphosphate (TFV-DP) vs. tenofovir disoproxil fumarate (TDF). No studies have yet compared TFV-DP in PBMC from lower than daily dosing between prodrugs, which has potential implications for event-driven preexposure prophylaxis and pharmacologic forgiveness. DESIGN: Two separate randomized, directly observed therapy (DOT) crossover studies (DOT-DBS and TAF-DBS) were conducted to mimic low, medium and high adherence. METHODS: HIV-negative adults were randomized to two 12-week DOT regimens of 33, 67 or 100% of daily dosing with emtricitabine (F)/TAF 200 mg/25 mg (TAF-DBS) or F/TDF 200 mg/300 mg (DOT-DBS), separated by a 12-week washout. PBMC steady-state concentrations (Css) of TFV-DP and FTC-TP were estimated using nonlinear mixed models and compared between F/TAF and F/TDF. RESULTS: Thirty-five participants contributed to 33% (n = 23), 67% (n = 23) and 100% (n = 23) of daily F/TAF regimens. Forty-four contributed to 33% (n = 15), 67% (n = 16) and 100% (n = 32) of daily F/TDF regimens. PBMC TFV-DP Css were 7.3 [95% confidence interval (95% CI): 6.4-8.2], 7.1 (5.9-8.2) and 6.7- (4.4-8.9) fold higher (P < 0.0001) following F/TAF vs. F/TDF; 593 vs. 81.7, 407 vs. 57.4, and 215 vs. 32.3 fmol/106 cells, respectively. TFV-DP was 2.6 (2.1-3.1) fold higher with 33% F/TAF vs. 100% F/TDF. Estimated half-lives (95% CI) of TFV-DP in PBMC were 2.9 (1.5-5.5) days for F/TAF and 2.1 (1.5-2.9) days for F/TDF. FTC-TP was similar in both studies (P = 0.119). CONCLUSION: F/TAF produced 6.7 to 7.3-fold higher TFV-DP in PBMC vs. F/TDF across adherence levels, supporting increased potency and pharmacologic forgiveness with F/TAF in the PBMC compartment.

Mechnetor: a web server for exploring protein mechanism and the functional context of genetic variants.

Advances in DNA sequencing and proteomics mean that researchers must now regularly interrogate thousands of positional gene/protein changes in order to find those relevant for potential clinical application or biological insights. The abundance of already known information on protein interactions, mechanism, and tertiary structure provides the possible means to understand these changes rapidly, though a careful and systematic integration of these diverse datasets is first needed. For this purpose, we developed Mechnetor, a tool that allows users to quickly explore and visualize integrated mechanistic data for proteins or interactions of interest. Central to the system is a careful cataloguing of diverse sources of protein interaction mechanism, and an efficient means to visualize interactions between relevant and/or known protein regions. The result is a finer resolution interaction network that provides more immediate clues as to points of intervention or mechanistic understanding. Users can import protein, interactions, genetic variants or post-translational modifications and see these data in the best known mechanistic context. We demonstrate the tool with topical examples in human genetic diseases and cancer genomics. The tool is freely available at: mechnetor.russelllab.org.

A comparison of covariate selection techniques applied to pre-exposure prophylaxis (PrEP) drug concentration data in men and transgender women at risk for HIV.

Pre-exposure prophylaxis (PrEP) containing antiretrovirals tenofovir disoproxil fumarate (TDF) or tenofovir alafenamide (TAF) can reduce the risk of acquiring HIV. Concentrations of intracellular tenofovir-diphosphate (TFV-DP) measured in dried blood spots (DBS) have been used to quantify PrEP adherence; although even under directly observed dosing, unexplained between-subject variation remains. Here, we wish to identify patient-specific factors associated with TFV-DP levels. Data from the iPrEX Open Label Extension (OLE) study were used to compare multiple covariate selection methods for determining demographic and clinical covariates most important for drug concentration estimation. To allow for the possibility of non-linear relationships between drug concentration and explanatory variables, the component selection and smoothing operator (COSSO) was implemented. We compared COSSO to LASSO, a commonly used machine learning approach, and traditional forward and backward selection. Training (N = 387) and test (N = 166) datasets were utilized to compare prediction accuracy across methods. LASSO and COSSO had the best predictive ability for the test data. Both predicted increased drug concentration with increases in age and self-reported adherence, the latter with a steeper trajectory among Asians. TFV-DP reductions were associated with increasing eGFR, hemoglobin and transgender status. COSSO also predicted lower TFV-DP with increasing weight and South American countries. COSSO identified non-linear relationships between log(TFV-DP) and adherence, weight and eGFR, with differing trajectories for some races. COSSO identified non-linear log(TFV-DP) trajectories with a subset of covariates, which may better explain variation and enhance prediction. Future research is needed to examine differences identified in trajectories by race and country.

Morphomolecular and pathological study of Scaphanocephalus sp. in new host Siganus argenteus in the Arabian Gulf.

In this study, Scaphanocephalus parasite (Platyhelminthes: Heterophyidae) metacercariae were found in Siganus argenteus (forktail rabbitfish or streamlined spinefoot) in the Arabian Gulf of Jubail province, Saudi Arabia. The findings may constitute new host and locality records for this parasite. Based on the number of black spots containing parasite cysts per fish, our study indicated that Siganus argenteus had high infection intensities of encysted metacercariae belonging to the genus Scaphanocephalus. Of the 3500 S. argenteus specimens examined, 800 (22.9%) showed multiple black cysts over the entire body surface, including the membranous parts of fins, while none were seen on the internal organs. The prevalence of infection was highest in summer (June-August) (8.8%). The excysted metacercariae differed morphologically from previously identified Scaphanocephalus spp. Molecular analysis of rDNA showed 100% identity with an unnamed Scaphanocephalus sp. reported in Caribbean fish. Therefore, our findings may indicate a new species of this previously rarely recorded fish parasite. The histopathological examination revealed that the encysted parasites were restricted to the dermal layer of the skin and surrounded by melanophores and a fibrous connective tissue capsule, with focal myositis and Zenker's necrosis in the underlying muscle tissue. The characteristically 'winged' parasite was clearly observed within the cysts. The high prevalence of Scaphanocephalus infection in siganid fish we detected requires further epidemiological study.

Histological and ultrastructural degenerative findings in the gluteus medius tendon after hip arthroplasty.

BACKGROUND: Despite gluteus medius (GMED) tendinosis being relatively common, its presence in association with hip osteoarthritis (OA) or total hip arthroplasty (THA) is not well studied. It was hypothesized that more tendon degeneration would be found in patients with OA of the hip and in those that had undergone THA than that in a control group. METHODS: One hundred patients were included between 2016 and 2019 and were included into 4 groups; the patients were undergoing revision surgery in two groups and primary THA in the other two groups; 22 patients had previously undergone primary THA through a direct lateral approach (involving sectioning of the GMED tendon), 24 patients had previously undergone primary THA through a posterior approach (leaving the GMED tendon intact), 29 patients had primary hip OA, and 25 patients who suffered a femoral neck fracture served as controls. Biopsies from the GMED tendon were obtained at the time of the primary THA or the hip revision surgery. The tendon biopsies were examined ultrastructurally and histologically. RESULTS: Ultrastructurally, the direct lateral and posterior revision groups had statistically significantly more collagen fibrils with smaller diameters compared with the fracture and primary THA groups. Moreover, the direct lateral revision group had more collagen fibrils with smaller diameters compared with the posterior revision group. Histologically, the direct lateral revision group had a higher total degeneration score (TDS) compared with the primary hip OA group. CONCLUSIONS: The GMED tendon shows more ultrastructural degeneration in patients who undergo hip revision arthroplasty than in patients with primary OA of the hip and control patients, who had suffered a femoral neck fracture. Furthermore, patients who had previously undergone primary THA through a direct lateral approach revealed more histological GMED tendon degeneration than patients who suffer primary hip OA.

Approaches to handling missing or "problematic" pharmacology data: Pharmacokinetics.

Missing or erroneous information is a common problem in the analysis of pharmacokinetic (PK) data. This may present as missing or inaccurate dose level or dose time, drug concentrations below the analytical limit of quantification, missing sample times, or missing or incorrect covariate information. Several methods to handle problematic data have been evaluated, although no single, broad set of recommendations for commonly occurring errors has been published. In this tutorial, we review the existing literature and present the results of our simulation studies that evaluated common methods to handle known data errors to bridge the remaining gaps and expand on the existing knowledge. This tutorial is intended for any scientist analyzing a PK data set with missing or apparently erroneous data. The approaches described herein may also be useful for the analysis of nonclinical PK data.

No significant histological or ultrastructural tendinosis changes in the hamstring tendon in patients with mild to moderate osteoarthritis of the knee?

PURPOSE: To investigate the periarticular degenerative changes of the knee joint in association with osteoarthritis (OA). More tendinosis was expected to be found in the semitendinosus tendon in patients with knee OA than in patients without knee OA. METHODS: Samples from 41 patients were included between January 2016 and October 2017. Twenty-one patients median age 53 (33-63) years with mild to moderate OA underwent high tibial osteotomy (HTO) and 20 patients median age 38 (31-57) years without OA underwent anterior cruciate ligament reconstruction (ACLR). Biopsies from the semitendinosus tendon were obtained at the time of surgery and examined histologically, morphologically and ultrastructurally using light and electron microscope. RESULTS: The histological evaluation of the semitendinosus tendon revealed the presence of more hemosiderin in the ACLR group. No significant morphological or ultrastructural differences were shown between patients in the HTO and ACLR group. CONCLUSION: Patients with mild and moderate medial compartment knee OA displayed no more degenerative changes in their semitendinosus tendon than patients without OA, as seen in both the light and the electron microscope. LEVEL OF EVIDENCE: III.

Individualized Adherence Benchmarks for HIV Pre-Exposure Prophylaxis.

Tenofovir diphosphate (TFV-DP) concentrations measured with dried blood spots (DBS) can be used to classify adherence to emtricitabine/tenofovir disoproxil fumarate (F/TDF) for HIV pre-exposure prophylaxis (PrEP). A TFV-DP of 700 fmol/punch was previously associated with high PrEP efficacy, and was estimated to represent ≥4 doses/week on average. However, interindividual variability in TFV-DP concentrations may lead to adherence misclassification and decrease the precision of adherence-efficacy relationships. The purpose of this analysis was to evaluate sources of TFV-DP variability to improve the precision of TFV-DP for adherence assessments by incorporating individual characteristics. Data and samples from a 36-week study of TFV-DP in DBS, collected biweekly, among 48 HIV-negative volunteers (25 Females/26 Caucasian/10 African American/14 Hispanic) receiving F/TDF at 33%, 67%, and 100% of daily dosing under directly observed therapy were used for analysis. The simplest pharmacokinetic model to describe TFV-DP accumulation with acceptable performance was a one-compartment constant input model. Covariates, including laboratory values and demographics were ranked in importance of their association with post hoc pharmacokinetic (PK) parameters using random forest analyses. Weight and platelet count were included in the final model and simulations were conducted to generate benchmarks for <2, 2-3, 4-5, and 6-7 doses/week. Based on these simulations, the previously established protective TFV-DP concentration of ≥700 fmol/punch was observed in those taking 2-3 (in individuals ≤110 kg) and ≥4 (in individuals >110 kg) doses/week, amounting to a much lower rate of misspecification (17% vs. 30%) with this individualized model versus previous interpretations. Incorporating body weight and platelet count improved the precision of TFV-DP concentrations for adherence assessments. Previous benchmarks were conservative, indicating that the pharmacological forgiveness of F/TDF may be higher than currently recognized and supports continued investigation of intermittent PrEP dosing regimens. Clinical Trial Registration number, NCT02022657.

Tenofovir Diphosphate Concentrations in Dried Blood Spots From Pregnant and Postpartum Adolescent and Young Women Receiving Daily Observed Pre-exposure Prophylaxis in Sub-Saharan Africa.

BACKGROUND: Intracellular tenofovir diphosphate (TFV-DP) concentration in dried blood spots (DBSs) is used to monitor cumulative pre-exposure prophylaxis (PrEP) adherence. We evaluated TFV-DP in DBSs following daily oral PrEP (emtricitabine 200 mg/tenofovir diphosphate 300 mg) among pregnant and postpartum adolescent girls and young women (AGYW). METHODS: Directly observed PrEP was administered for 12 weeks in a pregnancy (14-24 weeks' gestation, n = 20) and postpartum (6-12 weeks postpartum, n = 20) group of AGYW aged 16-24 years in sub-Saharan Africa. Weekly DBS TFV-DP was measured by validated liquid chromatography-tandem mass spectrometry assay. Week 12 TFV-DP distributions were compared between groups with Wilcoxon test. Population pharmacokinetic models were fit to estimate steady-state concentrations and create benchmarks for adherence categories. Baseline correlates of TFV-DP were evaluated. RESULTS: Median age was 20 (IQR, 19-22) years. Of 3360 doses, 3352 (>99%) were directly observed. TFV-DP median (IQR) half-life was 10 (7-12) days in pregnancy and 17 (14-21) days postpartum, with steady state achieved by 5 and 8 weeks, respectively. Observed median (IQR) steady-state TFV-DP was 965 fmol/punch (691-1166) in pregnancy versus 1406 fmol/punch (1053-1859) postpartum (P = .006). Modeled median steady-state TFV-DP was 881 fmol/punch (667-1105) in pregnancy versus 1438 fmol/punch (1178-1919) postpartum. In pooled analysis, baseline creatinine clearance was associated with observed TFV-DP concentrations. CONCLUSIONS: TFV-DP in African AGYW was approximately one-third lower in pregnancy than postpartum. These Population-specific benchmarks can be used to guide PrEP adherence support in pregnant/postpartum African women. CLINICAL TRIALS REGISTRATION: NCT03386578.