CLINICAL FEATURES AND SURGICAL OUTCOMES OF SCLERAL BUCKLE SURGERY FOR PRIMARY RHEGMATOGENOUS RETINAL DETACHMENT: Moorfields Buckle Study.

PURPOSE: Long-term study to evaluate the clinical and surgical outcomes of scleral buckle (SB) surgery for primary rhegmatogenous retinal detachment (RRD) at a large tertiary eye center. METHODS: Noncomparative, retrospective case series of 589 eyes of 569 patients with primary RRD who underwent SB surgery between 2004 and 2022 with a median follow-up of 6 months. The main outcome measures were best-corrected visual acuity, surgical outcomes, complications, and classification of RRD. RESULTS: At baseline, 447/589 (76.1%) round hole RRD, and 133/589 (22.7%) retinal dialysis RRD. Overall primary SB success rate was 83.7% for all retinal detachment subtypes, with round hole retinal detachment 84.8% and dialysis RRD 81.2%. Overall, the baseline best-corrected visual acuity was 0.42 logarithm of the minimum angle of resolution (logMAR) and the final best-corrected visual acuity was 0.26 logMAR ( P < 0.0001). In macula-off RRD, the best-corrected visual acuity significantly improved from 0.79 to 0.48 logMAR ( P < 0.0001). In patients with macula-on RRD, it improved from 0.19 to 0.12 logMAR ( P = 0.014). Binary logistic regression showed registrar surgeon grade (odds ratio [OR] 0.09, 95% confidence interval [CI] 0.01-0.55), and partial or complete posterior vitreous detachment (OR 0.21, 95% CI 0.10-0.49) was associated with reduced odds of primary success. Higher surgical failure was associated with low pre-fellowship SB surgeon experience ( P = 0.024). CONCLUSION: Favorable visual and functional outcomes have been reported in a large series of SB for primary retinal detachment, mainly for patients with round hole RRD and retinal dialysis RRD.

Unveiling the Antimicrobial and Larvicidal Potential of Butyrolactones and Orsellinic Acid Derivatives from the Morus alba-derived Fungus Aspergillus terreus via Integrated In vitro and In silico Approaches.

The emergence of multi-drug-resistant microbial strains spurred the search for antimicrobial agents; as a result, two distinct approaches were combined: four in vitro studies and four corresponding molecular docking investigations. Antituberculosis, anti-methicillin-resistant Staphylococcus aureus (anti-MRSA), antifungal, and larvicidal activities of the crude extract, two fractions, and seven isolated compounds from Aspergillus terreus derived from Morus alba roots were explored. The isolated compounds (5 butyrolactones and 2 orsellinic acid derivatives) showed potent to moderate antitubercular activity with MIC values ranging from 1.95 to 62.5 µg/mL (compared to isoniazid, 0.24 µg/mL) and promising anti-MRSA potential with inhibition zone diameters ranging from 8 to 25 mm. Additionally, the in silico study proved that the isolated compounds bind to the two corresponding proteins' active sites with high to moderate -(C-Docker interaction energies) and stable interactions. The isolated compounds displayed antifungal activities against different fungal strains at diverse degrees of activity, among them compound (8"S,9")-dihydroxy-dihydrobutyrolactone I eliciting the best antifungal activity. Meanwhile, all isolated compounds, fractions, and the crude extract demonstrated extremely selective potent to moderate activity against Cryptococcus neoformans. The isolated five butyrolactone derivatives could develop potential mosquito larvicidal agents as a result of promising docking outcomes in the larval enzyme carboxylesterase.

A comprehensive review on the medicinally valuable endosymbiotic fungi Penicillium chrysogenum.

Recently, it has been shown that metabolites derived from endosymbiotic fungi attracted high attention, since plenty of them have promising pharmaceutical applications. The variation of metabolic pathways in fungi is considered an optimistic source for lead compounds. Among these classes are terpenoids, alkaloids, polyketides, and steroids, which have proved several pharmacological activities, including antitumor, antimicrobial, anti-inflammatory, and antiviral actions. This review concludes the major isolated compounds from different strains of Penicillium chrysogenum during the period 2013-2023, together with their reported pharmacological activities. From literature surveys, 277 compounds have been identified from P. chrysogenum, which has been isolated as an endosymbiotic fungus from different host organisms, with specific attention paid to those showing marked biological activities that could be useful in the pharmaceutical industry in the future. This review represents documentation for a valuable reference for promising pharmaceutical applications or further needed studies on P. chrysogenum.

New Meroterpenoid Derivatives from the Pomegranate-Derived Endophytic Fungus Talaromyces purpureogenus.

In this study, we report the isolation of two new meroterpenoids, miniolutelide D (1) and miniolutelide E (13-epi-miniolutelide C) (2), along with two meroterpenoidal analogues (3 and 4) and two phenolic compounds (5 and 6) from the endophytic fungus Talaromyces purpureogenus derived from Punica granatum fruits. Their structures were elucidated using extensive MS, 1D, and 2D NMR spectroscopic analyses as well as by comparing with data in the literature. The absolute configurations of 1 and 2 were determined using TDDFT-ECD calculations. Antimicrobial activity was evaluated. Compound 5 displayed significant activity against methicillin-resistant Staphylococcus aureus strain ATCC 700699 and moderate activity against S. aureus strain ATCC 29213.

Cyclodepsipeptides: Isolation from Endophytic Fungi of Sarcophyton ehrenbergi and Verification of Their Larvicidal Activity via In-Vitro and In-Silico Studies.

Culex pipiens mosquitoes are vectors to many viruses and can transmit diseases such as filariasis and avian malaria. The present study evaluated the larvicidal activity of marine-derived endophytic fungi Aspergillus nomius and Aspergillus flavus from the soft coral Sarcophyton ehrenbergi along with two known cyclodepsipeptide compounds, scopularide A (1) and B (2), isolated from A. flavus extract, against third-instar larvae of C. pipiens, using distilled water as a negative control and toosenedanin as a positive control. The structures of the isolated compounds were confirmed by various spectroscopic analyses. The lethal concentrations (LC50 and LC90) were calculated by probit analysis. Scopularide A was the most potent after 96 h treatment, with LC50 and LC90 values of 58.96 and 994.31 ppm, respectively, and with 82.66% mortality at a concentration of 300 ppm. To unravel the biochemical mechanism of the tested extracts and compounds, their effects against protease, chitinase, phenoloxidases and lipase enzymes from the whole-body tissue of C. pipiens were evaluated after 72 h treatment at LC50 dose. Superior activity was observed for A. flavus extract against all tested enzymes. A molecular docking study was conducted for scopularide A and B on the four tested enzymes, to further verify the observed activity. Results revealed good binding affinities for both compounds as compared to the docked ligands, mainly via a number of hydrogen bonds. This was the first study to report the isolation of endophytic fungi A. flavus and A. nomius from the marine soft coral S. ehrenbergi. The endophytic fungal extract of A. flavus was found to be a promising source for a natural larvicidal agent against C. pipiens populations.

Postpartum vertebral artery dissection: case report and review of the literature.

BACKGROUND: Hypertensive disorders of pregnancy are associated with vascular complications, including ischemic stroke and cervical artery dissection. Vertebral artery dissection (VAD), however, is rare. We describe a 31-year-old female who presented with vertigo, nausea, and vomiting and was found to have a VAD. In addition, we discuss the presentation, differential diagnosis, and pathogenesis of this uncommon but clinically significant vascular event and summarize other cases of vertebral artery dissection described in the medical literature. CASE PRESENTATION: A 31-year-old Hispanic woman presented 10 days postpartum with a one-day history of vertigo, nausea, vomiting, and frontal headache. The patient's pregnancy course had been complicated by preeclampsia, chorioamnionitis, and iron-deficiency anemia, and her delivery was complicated by acute hemorrhage. Physical examination was significant for left leg ataxia. Laboratory studies showed marked thrombocytosis. Emergent computed tomography (CT) scan of the head was obtained and revealed a left cerebellar ischemic large vessel stroke. Subsequent CT angiography of the head and neck showed a left VAD. Based on correlation of the clinical history and laboratory and imaging findings, a diagnosis of vertebral artery dissection secondary to reactive (secondary) thrombocytosis from overlapping iron-deficiency anemia and acute hemorrhage was established. The patient was started on a heparin infusion and experienced significant improvement after a four-day hospitalization. CONCLUSION: VAD is a rare but important cause of neurologic symptoms in the postpartum period and should be considered in the differential diagnosis for women who present with headache and/or vertigo. Women aged 30 years or older and those with a history of a hypertensive disorder of pregnancy are at particularly high risk. Prompt diagnosis and management of VAD is essential to ensure favorable outcomes.

Chemical Diversity in Species Belonging to Soft Coral Genus Sacrophyton and Its Impact on Biological Activity: A Review.

One of the most widely distributed soft coral species, found especially in shallow waters of the Indo-Pacific region, Red Sea, Mediterranean Sea, and also the Arctic, is genus Sacrophyton. The total number of species belonging to it was estimated to be 40. Sarcophyton species are considered to be a reservoir of bioactive natural metabolites. Secondary metabolites isolated from members belonging to this genus show great chemical diversity. They are rich in terpenoids, in particular, cembranoids diterpenes, tetratepenoids, triterpenoids, and ceramide, in addition to steroids, sesquiterpenes, and fatty acids. They showed a broad range of potent biological activities, such as antitumor, neuroprotective, antimicrobial, antiviral, antidiabetic, antifouling, and anti-inflammatory activity. This review presents all isolated secondary metabolites from species of genera Sacrophyton, as well as their reported biological activities covering a period of about two decades (1998-2019). It deals with 481 metabolites, including 323 diterpenes, 39 biscembranoids, 11 sesquiterpenes, 53 polyoxygenated sterols, and 55 miscellaneous and their pharmacological activities.

The MDM4/MDM2-p53-IGF1 axis controls axonal regeneration, sprouting and functional recovery after CNS injury.

Regeneration of injured central nervous system axons is highly restricted, causing neurological impairment. To date, although the lack of intrinsic regenerative potential is well described, a key regulatory molecular mechanism for the enhancement of both axonal regrowth and functional recovery after central nervous system injury remains elusive. While ubiquitin ligases coordinate neuronal morphogenesis and connectivity during development as well as after axonal injury, their role specifically in axonal regeneration is unknown. Following a bioinformatics network analysis combining ubiquitin ligases with previously defined axonal regenerative proteins, we found a triad composed of the ubiquitin ligases MDM4, MDM2 and the transcription factor p53 (encoded by TP53) as a putative central signalling complex restricting the regeneration program. Indeed, conditional deletion of MDM4 or pharmacological inhibition of MDM2/p53 interaction in the eye and spinal cord promote axonal regeneration and sprouting of the optic nerve after crush and of supraspinal tracts after spinal cord injury. The double conditional deletion of MDM4-p53 as well as MDM2 inhibition in p53-deficient mice blocks this regenerative phenotype, showing its dependence upon p53. Genome-wide gene expression analysis from ex vivo fluorescence-activated cell sorting in MDM4-deficient retinal ganglion cells identifies the downstream target IGF1R, whose activity and expression was found to be required for the regeneration elicited by MDM4 deletion. Importantly, we demonstrate that pharmacological enhancement of the MDM2/p53-IGF1R axis enhances axonal sprouting as well as functional recovery after spinal cord injury. Thus, our results show MDM4-MDM2/p53-IGF1R as an original regulatory mechanism for CNS regeneration and offer novel targets to enhance neurological recovery.media-1vid110.1093/brain/awv125_video_abstractawv125_video_abstract.

Modulation of GABAA receptor signaling increases neurogenesis and suppresses anxiety through NFATc4.

Correlative evidence suggests that GABAergic signaling plays an important role in the regulation of activity-dependent hippocampal neurogenesis and emotional behavior in adult mice. However, whether these are causally linked at the molecular level remains elusive. Nuclear factor of activated T cell (NFAT) proteins are activity-dependent transcription factors that respond to environmental stimuli in different cell types, including hippocampal newborn neurons. Here, we identify NFATc4 as a key activity-dependent transcriptional regulator of GABA signaling in hippocampal progenitor cells via an unbiased high-throughput genome-wide study. Next, we demonstrate that GABAA receptor (GABAAR) signaling modulates hippocampal neurogenesis through NFATc4 activity, which in turn regulates GABRA2 and GABRA4 subunit expression via binding to specific promoter responsive elements, as assessed by ChIP and luciferase assays. Furthermore, we show that selective pharmacological enhancement of GABAAR activity promotes hippocampal neurogenesis via the calcineurin/NFATc4 axis. Importantly, the NFATc4-dependent increase in hippocampal neurogenesis after GABAAR stimulation is required for the suppression of the anxiety response in mice. Together, these data provide a novel molecular insight into the regulation of the anxiety response in mice, suggesting that the GABAAR/NFATc4 axis is a druggable target for the therapy of emotional disorders.

Nuclear factor of activated T cells (NFATc4) is required for BDNF-dependent survival of adult-born neurons and spatial memory formation in the hippocampus.

New neurons generated in the adult dentate gyrus are constantly integrated into the hippocampal circuitry and activated during encoding and recall of new memories. Despite identification of extracellular signals that regulate survival and integration of adult-born neurons such as neurotrophins and neurotransmitters, the nature of the intracellular modulators required to transduce those signals remains elusive. Here, we provide evidence of the expression and transcriptional activity of nuclear factor of activated T cell c4 (NFATc4) in hippocampal progenitor cells. We show that NFATc4 calcineurin-dependent activity is required selectively for survival of adult-born neurons in response to BDNF signaling. Indeed, cyclosporin A injection and stereotaxic delivery of the BDNF scavenger TrkB-Fc in the mouse dentate gyrus reduce the survival of hippocampal adult-born neurons in wild-type but not in NFATc4(-/-) mice and do not affect the net rate of neural precursor proliferation and their fate commitment. Furthermore, associated with the reduced survival of adult-born neurons, the absence of NFATc4 leads to selective defects in LTP and in the encoding of hippocampal-dependent spatial memories. Thus, our data demonstrate that NFATc4 is essential in the regulation of adult hippocampal neurogenesis and identify NFATc4 as a central player of BDNF-driven prosurvival signaling in hippocampal adult-born neurons.

Cytotoxic naphtho- and benzofurans from an endophytic fungus Epicoccum nigrum Ann-B-2 associated with Annona squamosa fruits.

Chemical exploration of the total extract derived from Epicoccum nigrum Ann-B-2, an endophyte associated with Annona squamosa fruits, afforded two new metabolites, epicoccofuran A (1) and flavimycin C (2), along with four known compounds namely, epicocconigrone A (3), epicoccolide B (4), epicoccone (5) and 4,5,6-trihydroxy-7-methyl-1,3-dihydroisobenzofuran (6). Structures of the isolated compounds were elucidated using extensive 1D and 2D NMR along with HR-ESI-MS. Flavimycin C (2) was isolated as an epimeric mixture of its two diastereomers 2a and 2b. The new compounds 1 and 2 displayed moderate activity against B. subtilis, whereas compounds (2, 3, 5, and 6) showed significant antiproliferative effects against a panel of seven different cancer cell lines with IC50 values ranging from 1.3 to 12 µM.

Cytotoxic and antimicrobial mycophenolic acid derivatives from an endophytic fungus Penicillium sp. MNP-HS-2 associated with Macrozamia communis.

Macrozamia communis and its associated endophytic fungi are untapped sources of bioactive metabolites with great potential for medicinal exploitation. Chemical investigation of the mycelial extract derived from an endophytic fungus Penicillium sp. MNP-HS-2 associated with M. communis fruit afforded four mycophenolic acid derivatives recognized as previously undescribed natural products (1-4), together with nine known metabolites (5-13). Chemical structures of isolated compounds were determined based on extensive spectroscopic analyses, including 1D/2D NMR and HRESIMS. The absolute stereochemistry of alternatain E (1) was unambiguously established by comparing its experimental and calculated time-dependent density functional theory electronic circular dichroism spectra (TDDFT-ECD). All isolated compounds were assessed for their antimicrobial and cytotoxic activities, where mycophenolic acid methyl ester (7), displayed significant cytotoxic activity against seven different cell lines with IC50 values in the low micromolar to nanomolar range. Mycophenolene A (3) exhibited significant antibacterial activity against Staphylococcus aureus (MIC = 2.1 µg/mL).

Comparative metabolomics study on the secondary metabolites of the red alga, Corallina officinalis and its associated endosymbiotic fungi.

Marine endosymbionts have gained remarkable interest in the last three decades in terms of natural products (NPs) isolated thereof, emphasizing the chemical correlations with those isolated from the host marine organism. The current study aimed to conduct comparative metabolic profiling of the marine red algae Corallina officinalis, and three fungal endosymbionts isolated from its inner tissues namely, Aspergillus nidulans, A. flavipes and A. flavus. The ethyl acetate (EtOAc) extracts of the host organism as well as the isolated endosymbionts were analyzed using ultra-high performance liquid chromatography coupled to high resolution tandem mass spectrometry (UHPLC-MS/MS)in both positive and negative ion modes, applying both full scan (FS) and all ion fragmentation (AIF) modes. Extensive interpretation of the LC-MS/MS spectra had led to the identification of 76 metabolites belonging to different phytochemical classes including alkaloids, polyketides, sesquiterpenes, butyrolactones, peptides, fatty acids, isocoumarins, quinones, among others. Metabolites were tentatively identified by comparing the accurate mass and fragmentation pattern with metabolites previously reported in the literature, as well as bioinformatics analysis using GNPS. A relationship between the host C. officinalis and its endophytes (A. flavus, A. nidulans, and A. flavipes) was discovered. C. officinalis shares common metabolites with at least one of the three endosymbiotic fungi. Some metabolites have been identified in endophytes and do not exist in their host. Multivariate analysis (MVA) revealed discrimination of A. flavipes from Corallina officinalis and other associated endophytic Aspergillus fungi (A. flavus and A. nidulans).

Useful energy, economic and reduction of greenhouse gas emissions assessment of solar water heater and solar air heater for heating purposes in Gaza, Palestine.

This study investigated the crisis of energy from which Gaza has been suffering over the past years. It ventured to highlight the growing needs for energy and the urging need to use renewable and sustainable sources of energy such as solar thermal energy. Much specifically, it gave much importance to the solar water heater (SWH) as well as the solar air heater (SAH). These two important tools rely on clean and renewable source of energy, and their use in the Gaza Strip would greatly help in bringing about an environmental conservation and sustainable economy. The result obviously shows that both SWH and SAH systems are very suitable for space heating for buildings. The maximum annual heating energy gained is 20360.7 kWh at an inclination angle of the solar collector of 30° for SWH. While for SAH the best value of heating delivered was 19268.9 kWh at a tilt angle of 45°. Besides, the result exposes that the use of SWH and SAH systems can potentially save up to $3461.3 and $3275.7 respectively of energy cost annually. The payback achieved on the investment in SWH and SAH is 4.4 and 4 years respectively. Additionally, the utilization of SWH and SAH systems can ultimately save energy as well as potentially reduce emission of air pollution. For instance, using SWH and SAH can reduce 17306.6 and 16378.57 kg/year of CO2 emissions respectively.

Epiphyseal osteoid osteoma of the proximal tibial epiphysis treated by CT-guided radiofrequency ablation: A case report.

Osteoid osteoma is a benign bone tumor commonly occurring in the diaphysis and metaphysis of long bones. Only a few cases were reported in the literature about the rare location of epiphyseal osteoid osteoma and all were treated surgically. Herein, we report a rare case of an epiphyseal tibial osteoid osteoma, in a 14-year-old boy, which was initially diagnosed by imaging and confirmed by histopathology. To the best of our knowledge, this is the first case of an epiphyseal osteoid osteoma treated successfully by CT-guided radiofrequency ablation in a pediatric patient with a good outcome and no detrimental effects. The case highlights the rarity of such presentation, the importance of early imaging and diagnosis, and the success of CT-guided radiofrequency ablation in the treatment of epiphyseal osteoid osteoma.

Austalide derivative from marine-derived Aspergillus sp. and evaluation of its cytotoxic and ADME/TOPKAT properties.

In-depth chemical investigation of an ethyl acetate extract of Aspergillus sp. isolated from the soft coral Sinularia species resulted in the isolation of one new meroterpenoid, austalide Z (1), one known austalide W (2), six known prenylated indole diketopiperazine alkaloids (3-8), and phthalic acid and its ethyl derivative (9-10). The structures were established by means of 1D and 2D NMR (one- and two-dimensional nuclear magnetic resonance) experiments supported by UV analysis and ESI-MS (electrospray ionization mass spectrometry). In vitro cytotoxic evaluation was performed against the Caco-2 cancer cell line using the MTT assay, which showed that the examined compounds had weak to moderate activities, with the new meroterpenoid austalide Z (1) displaying an IC50 value of 51.6 µg mL-1. ADME/TOPKAT (absorption, distribution, metabolism, excretion, and toxicity) predication performed in silico showed that most of the isolated compounds possessed reasonable pharmacokinetic, pharmacodynamic, and toxicity properties. Thus, it can be concluded that Aspergillus sp. could act as a source of drug leads for cancer prevention with promising pharmacokinetic and pharmacodynamic properties and thus could be incorporated in pharmaceutical dosage forms.

Single-tuned passive filter (STPF) for mitigating harmonics in a 3-phase power system.

Numerous integrals of the fundamental frequency are known as harmonics and can be found in power systems or electrical circuitry systems. Non-linear loads occasionally drain current or contains a varying impedance with each period of the AC voltage are often responsible for power system harmonics. This can result in system overheating, system losses, and equipment or system damage. In order to achieve the IEEE 519 power quality standard, filters are routinely employed to lower harmonic levels. In this work, we designed a single tuned passive filter (STPF) to minimize harmonics of sequence 5th, 7th, 11th, 13th, 17th, and 19th in a three (3) phase power system. The measurements were taken at the point of common coupling. To test the filter performance, the system and STPF were designed in MATLAB/Simulink, and the simulated results produced without and with STPF were compared. The [Formula: see text] was reduced from 14.93% down to 4.87% when STPF was connected which is within the IEEE 519-2022 standard; proving that the STPF was effective in decreasing the harmonics to the desired level.

Hyponatraemic seizure secondary to primary polydipsia following urological surgery.

An 82-year-old man presented to the emergency department with delirium, vomiting and an initial hyponatraemia of 112 mmol/L the day after successful transurethral vaporisation of the prostate. He had a tonic-clonic seizure in the acute surgical unit and was managed subsequently in the intensive care unit with a controlled rate of hypertonic saline. Initial work-up for the cause of hyponatraemia revealed a low urine osmolality, suggestive of relative excess water intake. Detailed examination of the operation notes revealed no discrepancy between intraoperative irrigating fluid input and output. Careful collateral history revealed that the patient had drunk 8 L of water in the 24 hours following the operation, after taking advice to 'drink plenty of water' literally. This case highlights the importance of conveying specific advice to patient, the lower incidence of transurethral resection syndrome in resections using saline as an irrigation fluid and outlines the pathway for investigation and management for hyponatraemia.

COVID-19 and liver diseases, what we know so far.

Coronavirus disease 2019 (COVID-19) pneumonia outbreak started in December 2019. On March 12, 2020, the World Health Organization (WHO) declared that the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) constitutes a pandemic, and as of May 2021, SARS-CoV-2 has infected over 167.3 million patients, including 3.4 million deaths, reported to WHO. In this review, we will focus on the relationship between SARS-CoV-2 infection and the liver. We will discuss how chronic liver diseases affect the COVID-19 disease course and outcomes. We will also discuss the SARS-CoV-2 effects on the liver, mechanisms of acute liver injury, and potential management plans.

Cytogenetic profile of adult acute myeloid leukemia in Egypt: a single-center experience.

BACKGROUND: Acute myeloid leukemia (AML) is a diverse disease characterized by the expansion of blasts of myeloid lineage. Cytogenetic testing is the cornerstone for risk stratification of AML patients. Geographical and environmental factors may play a very important role in the development of leukemia and several differences in genetic profile may be seen among different ethnicities. In our study, we evaluated cytogenetic findings of adult AML patients in South Egypt. METHODS: Cytogenetic testing (karyotyping and M-FISH) was performed for 120 adult patients with AML. Twenty metaphases were analyzed for each patient. RESULTS: In our study, the median age of AML patients was 36.5 years, with an age range between 18 and 86 years. 56.7% of patients had normal karyotypes and 43.3% of patients had clonal cytogenetic abnormalities. t (15;17) was the most detected structural abnormality, and + 8 was the most detected numerical abnormality. Regarding cytogenetic risk stratification, 65% of patients were in the intermediate-risk category. CONCLUSION: The cytogenetic profile of AML patients in our locality showed some differences and some similarities with cytogenetic profiles in different Arab, Asian and Western countries. Further studies are needed using advanced techniques such as next-generation sequencing and optical genome mapping to elucidate more ethnic and geographic genetic heterogeneity among different countries.