A multifunctional N-GO/PtCo nanocomposite bridged carbon fiber interface for the electrochemical aptasensing of CA15-3 oncomarker.

The development of integrated analytical devices is crucial for advancing next-generation point-of-care platforms. Herein, we describe a facile synthesis of a strongly catalytic and durable Nitrogen-doped graphene oxide decorated platinum cobalt (NGO-PtCo) nanocomposite that is conjugated with target-specific DNA aptamer (i-e. MUC1) and grown on carbon fiber. Benefitting from the combined features of the high electrochemical surface area of N-doped GO, high capacitance and stabilization by Co, and high kinetic performance by Pt, a robust, multifunctional, and flexible nanotransducer surface was created. The designed platform was applied for the specific detection of a blood-based oncomarker, CA15-3. The electrochemical characterization proved that nanosurface provides a highly conductive and proficient immobilization support with a strong bio-affinity towards MUC1 aptamer. The specific interaction between CA15-3 and the aptamer alters the surface properties of the aptasensor and the electroactive signal probe generated a remarkable increase in signal intensity. The sensor exhibited a wide dynamic range of 5.0 × 10-2 -200 U mL-1, a low limit of detection (LOD) of 4.1 × 10-2 U mL-1, and good reproducibility. The analysis of spiked serum samples revealed outstanding recoveries of up to 100.03 %, by the proposed aptasensor. The aptasensor design opens new revelations in the reliable detection of tumor biomarkers for timely cancer diagnosis.

Cryptogenic Stroke Complicated by Infective Endocarditis: Exploring the Multidisciplinary Interplay.

Infective endocarditis (IE) poses a significant clinical challenge due to its non-specific symptoms and variety of complications. Complications can include ischaemic stroke, valve dysfunction, discitis, and osteomyelitis, highlighting the complexity of IE management. We present a case of a male in his 40s, admitted with an ischaemic stroke, eventually being found to have underlying IE with a plethora of complications. This case highlights the importance of collaboration among specialists to form a multidisciplinary team, which is essential for the effective delivery of care. Furthermore, there is a critical need to explore the psychological impact of IE on patient outcomes, advocating for a holistic approach that considers psychological well-being alongside medical management. Future research should address these underexplored facets to improve patient care and outcomes in IE.

Brachyolmia, dental anomalies and short stature (DASS): Phenotype and genotype analyses of Egyptian and Pakistani patients.

Brachyolmia is a heterogeneous group of developmental disorders characterized by a short trunk, short stature, scoliosis, and generalized platyspondyly without significant deformities in the long bones. DASS (Dental Abnormalities and Short Stature), caused by alterations in the LTBP3 gene, was previously considered as a subtype of brachyolmia. The present study investigated three unrelated consanguineous families (A, B, C) with Brachyolmia and DASS from Egypt and Pakistan. In our Egyptian patients, we also observed hearing impairment. Exome sequencing was performed to determine the genetic causes of the diverse clinical conditions in the patients. Exome sequencing identified a novel homozygous splice acceptor site variant (LTBP3:c.3629-1G > T; p. ?) responsible for DASS phenotypes and a known homozygous missense variant (CABP2: c.590T > C; p.Ile197Thr) causing hearing impairment in the Egyptian patients. In addition, two previously reported homozygous frameshift variants (LTBP3:c.132delG; p.Pro45Argfs*25) and (LTBP3:c.2216delG; p.Gly739Alafs*7) were identified in Pakistani patients. This study emphasizes the vital role of LTBP3 in the axial skeleton and tooth morphogenesis and expands the mutational spectrum of LTBP3. We are reporting LTBP3 variants in seven patients of three families, majorly causing brachyolmia with dental and cardiac anomalies. Skeletal assessment documented short webbed neck, broad chest, evidences of mild long bones involvement, short distal phalanges, pes planus and osteopenic bone texture as additional associated findings expanding the clinical phenotype of DASS. The current study reveals that the hearing impairment phenotype in Egyptian patients of family A has a separate transmission mechanism independent of LTBP3.

GC-MS Analysis of Persicaria bistorta: Uncovering the Molecular Basis of Its Traditional Medicinal Use.

Persicaria bistorta is a perennial herb used traditionally in treating various ailments, including diarrhea, abdominal pain, and bleeding. In this study, we used gas chromatography-mass spectrometry (GC-MS) analysis to identify the chemical composition of Persicaria bistorta. The GC-MS analysis revealed the presence of several compounds, including flavonoids, tannins, saponins, and alkaloids. Among those, the most important from medicinal points of view are ethyl oleate (3%), cyclotetradecane (4.74%), dodecanoic acid (4.69%), hexadecanoic acid (5.61%), tetradecane (5.25%), cis-13-octadecenoic acid (10.91%), and bis(2-ethylhexyl) phthalate (32%). The GC-MS analysis of ethanolic fraction of Persicaria bistorta involved in antibacterial activity showed about 18 compounds. Among those, the most important from a medicinal and nutritional point of view are bis(2-ethylhexyl) phthalate (42.20%), 6-octadecenoic acid methyl ester, (Z)- (10.37%), ethyl oleate (6.84%), hexadecanoic acid methyl ester (6.67%), and methyl ester and oleic acid (5.27%). Reported biological antibacterial activity has shown that the main compound determined in both extracts was bis(2-ethylhexyl) phthalate, which has higher peak area percentage in ethanolic extract than in ethyl acetate fraction. Some oily compounds important for health because of their cis-conformation were also revealed in the given study like ethyl oleate and oleic acid. Overall, results suggest that Persicaria bistorta may have therapeutic potential and warrant further investigation. Further research is needed to confirm the efficacy and safety of Persicaria bistorta as a natural medicine and determine its active compounds' mechanisms of action.

Prevalence and difference of COVID-19 symptoms, post-COVID conditions and duration of illness among the vaccinated and unvaccinated population: a cross-sectional study in Peshawar.

Studies on coronavirus disease 2019 (COVID-19) symptoms, post-coronavirus disease (COVID) conditions, and vaccination outcomes in Pakistan are limited and inconsistent. The study investigated differences in symptoms and post-COVID conditions between vaccinated and unvaccinated individuals and the impact of vaccination on illness duration based on existing literature. Methods: The study was a 3-month cross-sectional study conducted in Peshawar, Pakistan. It targeted individuals aged 16 and above who had contracted COVID-19 at least once during the recent pandemic, regardless of gender, and confirmed through reverse transcriptase polymerase chain reaction testing. The sample size was 250, determined using the WHO sample size calculator. Data were collected through questionnaires after obtaining verbal consent and analyzed using IBM SPSS version 26, taking into account their vaccination status along with other important variables. Results: Among the 250 respondents, 143 (57.2%) were unvaccinated, while 107 (42.8%) were vaccinated at the time of contracting COVID-19. Unvaccinated subjects developed a greater variety of symptoms that lasted for longer durations (P<0.001) with symptoms like dyspnea [55 (38.5%, P=0.011)], anosmia [76 (53.1%, P=0.001)], and chest pain [24 (16.8%, P=0.029)] occurring at greater percentages. Sixty-one (42.7%) unvaccinated subjects reported post-COVID conditions as opposed to 29 (27.1%) among the vaccinated group [P=0.011; odds ratio (OR)=0.5; 95% CI=0.29-0.86]. Conclusion: The study found that COVID-19 vaccination can reduce the duration and frequency of symptoms, as well as post-COVID conditions. This is the first research of its kind conducted in Peshawar, Pakistan, and may serve as a foundation for future research in this demographic.

A novel frameshift variant in UBA2 causing split-hand/foot malformations in a Pakistani family.

Split-hand/foot malformation (SHFM) shows diverse heterogeneity and manifests with reduced penetrance and variable expressivity. This study investigated the underlying genetic cause of a family segregating SHFM. Exome sequencing followed by Sanger sequencing identified a novel single nucleotide heterozygous variant (NC_000019.9 (NM_005499.3):c.1118del) in UBA2 cosegregating in the family in an autosomal dominant manner. Our findings conclude that reduced penetrance and variable expressivity are the two remarkable and unusual features of SHFM.

Discovering the anti-diabetic potential of pomegranate peel metabolites by examining molecular interplay with the thioredoxin-interacting protein.

Introduction: Medicinal plants like Punica granatum (pomegranate) have traditional uses against diabetes, inflammation and other diseases. The study was initiated to get an insight into the interaction tendency of P. granatum derived compounds with diabetes associated human thioredoxin-interacting protein (TXNIP). High glucose in diabetes induces production of TXNIP resulting in ß-cells apoptosis. Its inhibition might reduce the diabetes incidence. Methods: To elucidate the therapeutic potential of P. granatum peel against diabetes through GC-MS based identification of extracted compounds followed by application of computational algorithms. P. granatum peel extracts were screened for antioxidant, anti-inflammatory, anti-diabetic, antimicrobial and wound healing properties. Phytochemical and GC-MS based analysis were performed to identify the bioactive compounds. Molecular docking analysis was performed by Auto Dock Vina to predict the binding tendency of P. granatum derived compounds with TXNIP. Results and Discussion: The peel exhibited antioxidant, anti-inflammatory and anti-diabetic activities, which were attributed to phytochemicals like phenols, tannins and steroids. GC-MS analysis identified 3,5-octadien-2-one, 1H-pyrrole -2,5-dione, Beta-D-lyxofuranoside, 5-O-(beta-D-lyxofuranosyl)-decyl, diethyl phthalate, 9-octadecenoic acid (Z)-, methyl ester, hexadecanoic acid, methyl ester, n-hexadecanoic acid, tetradecane, 2,6,10-trimethyl, bis (2-ethylhexyl) phthalate, decane, 3,8-dimethyl, 9-octadecenoic acid (Z)-, methyl ester and bis (2-ethylhexyl) phthalate in P. granatum peel extracts. Docking analysis revealed high binding affinities of bis (2-ethylhexyl) phthalate and 9-octadecenoic acid with TXNIP i.e., -4.5 and -5.0 kcal/mol, respectively, reflecting these compounds as potent antidiabetic agents. This study validates the traditional uses of P. granatum peel and demonstrates how computational approaches can uncover pharmacologically active phytochemicals. The results suggest P. granatum peel is a promising source of novel therapeutics against diabetes, inflammation, and oxidation. Further studies on the optimization of identified ligands are warranted.

Trypsin Inhibitor Isolated From Glycine max (Soya Bean) Extraction, Purification, and Characterization.

The current study aims to isolate, purify, and characterize the trypsin inhibitor protein from seeds of soya beans, scientifically known as Glycine max. Its seeds were ground, and the powder was soaked several times using n-hexane. It was added to phosphate buffer saline (PBS) followed by filtration and centrifugation of the PBS dissolved extract. The supernatant was subjected to ammonium sulfate precipitation and about six fractions, 30% to 80% were prepared. The centrifuged pellets obtained from each fraction were dialyzed and run on SDS-PAGE. The trypsin inhibitor protein was precipitated and characterized in 30% pellet and molecular weight was 21.5 kDa compared to protein ladder (ThermoFisher 10-170 kDa). GC-MS analysis revealed the steroid derivatives such as stigmasterol, campesterol, beta-sitosterol, and gamma-tocopherol. Glycine max trypsin inhibitor could be used as a plant-derived drug to overcome the over-activation of trypsin without its real substrate (proteins) becoming activated and start auto digestion leading to pancreatitis.

Brugada Syndrome Misdiagnosed As Acute Myocardial Infarction: A Case Report.

Brugada syndrome (BrS) is an autosomal-dominant condition mainly caused by defects in sodium channels causing ST-segment elevation in electrocardiograms (ECGs) in the V1 and V2 precordial leads, with ventricular tachyarrhythmias due to premature ventricular contractions, which increases the risk of sudden cardiac death. BrS usually presents in adulthood, with an average age of presentation of 41 years. In this article, we describe a case of BrS diagnosed in a 36-year-old male having sudden cardiac arrest with no comorbidities such as hypertension, diabetes mellitus, smoking, or any valvular disease history. We then explain the ECG-based diagnosis, signs and symptoms, presentation at the emergency department, and treatment options.

A Rare Case of Hereditary Hemorrhagic Telangiectasia: A Case Report.

Hereditary hemorrhagic telangiectasia (HHT), also known as Osler-Weber-Rendu syndrome, is a very rare autosomal dominant genetic disorder that leads to abnormal blood vessel formation in the skin, mucus membranes (called telangiectasia), and organs such as the lung, liver, and brain. It occurs due to a mutation in one of the ACVRL1, ENG, and SMAD4 genes, which code for the formation of blood vessels. The most common symptom is recurring nosebleed (epistaxis; due to rupture of nasal mucosal telangiectasia), which begins in childhood and affects about 90-95% of people with HHT. Other common signs and symptoms include punctate, linear, or splinter-like telangiectasias on the upper body, oral mucosa, or nail beds, gastrointestinal bleeding, and iron deficiency anemia. The diagnostic criteria currently in use are the Curaçao criteria. The diagnosis is made by clinical screening (e.g., history and physical exam), baseline investigations (complete blood count, hemoglobin, hematocrit, and ferritin level), genetic testing, and detailed medical imaging to detect visceral arteriovenous malformations (AVMs) such as esophagogastroduodenoscopy, colonoscopy, multiphase contrast CT, computed tomography angiography (CTA or CT Angio), magnetic resonance angiography (MRA), chest X-ray, Doppler ultrasonography, liver biopsy, and cerebral angiography. Management includes intravenous iron therapy or blood transfusion, antifibrinolytics (e.g tranexamic acid), ablation therapies (e.g. laser treatment, radiofrequency ablation, electrosurgery, sclerotherapy, and argon plasma coagulation), and systemic anti-angiogenic agents (e.g. thalidomide, bevacizumab). In this report, we present the case of a 22-year-old man from Swabi, Pakistan, with a history of recurrent epistaxis (nosebleed) from childhood, who presented with multiple episodes of melena (blood in stool), fatigue, palpitation, and iron deficiency anemia for five years. Multiple esophagogastroduodenoscopies (OGDs) and colonoscopies were done over the years, which showed AVM in the antrum and fundus of the stomach, duodenum, and colon, and a diagnosis of HHT was made. CTA and exploratory laparotomy showed ileal loop hemangiomas. He was managed with multiple blood transfusions, argon plasma coagulation (APC) for the AVMs, oral thalidomide, and steroids. Despite therapy, the patient had intermittent episodes of blood in stool and low blood counts. During his stay in Hayatabad Medical Complex (HMC), the patient was managed with high-frequency blood transfusion and bevacizumab (systemic anti-angiogenic agent). A dramatic reduction in the number of required transfusions and improvement in the patient's bloodlines and symptoms was noted. This case highlights the importance of endoscopic methods for the timely diagnosis of HHT and its management with intravenous bevacizumab.

Isolation and characterization of phytochemicals from ethyl acetate fraction of Solanum nigrum using GC-MS.

Solanum nigrum plant has rich therapeutic potential and different developed countries utilize this plant as a chief element for oriental medicinal practice including cancer therapy. The current study determines the isolation and purification of S. nigrum bioactive constituents through column chromatography from ethyl acetate extract of the plant followed by the Gas Chromatography-Mass Spectroscopy (GC-MS) to analyze the isolated compounds Different gradient elutions followed by thin layer chromatography of collected fractions were done and structural analysis of the isolated compounds was performed following GCMS analysis, More specifically the compounds were identified as 1, 2 benzene dicarboxylic acid, diisooctyl ester (95%) and as Bis (2-Ethylhexyl) phthalate (84%) along with 3 hydroxy 4 carboxy 2 methyl 6 pyridine (58%) with reference to chemical abstract service which may be responsible for its pharmacological properties. According to the best information available, no documented information exists regarding GC-MS based identification of the isolated chemical compounds from the S. nigrum. Present findings will help in exploring the therapeutic potential of 1, 2 benzene dicarboxylic acid, diisooctyl ester (95%), Bis (2-Ethylhexyl) phthalate (84%) and 3 hydroxy 4 carboxy 2 methyl 6 pyridine (58%) will be helpful in the development of new composites in pharmaceutical fields.

Response of Iron Deficiency Markers to Blood Lead Levels and Synergistic Outcomes at Prenatal Stage.

Lead may be passed on from a mother to their unborn fetus. If she has been exposed to lead for an extended period, the lead deposited in their bones can be stimulated to be released into the bloodstream during gestation. This study was planned to examine blood lead level at the prenatal stage and its response to markers of iron deficiency during gestation. We collected 396 samples during the second trimester of gestation from women age 19 to 45 years. Hematological markers including hemoglobin, hepcidin, total iron-binding capacity (TIBC), ferritin, and blood iron were analyzed. For the detection of blood lead, we used Atomic absorption spectroscopy. The mean blood lead level of the control group was 3.25 ± .407 µg/dL, and in the iron deficiency group, it was 7.96 ± .502 µg/dL. At the same time, the women with iron deficiency anemia showed 22.12 ± 1.02 µg/dL of mean blood lead. Pearson's approach showed a non-significant negative correlation between blood lead and hepcidin, while hemoglobin, total iron-binding capacity, ferritin, and serum iron showed a significant (.01) negative correlation with blood lead. Blood lead has no direct effect on iron deficiency markers. In contrast, iron deficiency contributes to an increase in lead accumulation during pregnancy. Iron and lead both have an impact on the heme-biosynthetic pathways. The study revealed that pre-existing iron deficiency is connected with increased lead intake and can negatively impact health in gestational females.

Medicinal plants show remarkable antiproliferative potential in human cancer cell lines.

Molecules isolated and identified from plant origin are used to manufacture most chemotherapeutic drugs for cancer treatment. We assumed that these plant extracts contain prolific bioactive compounds with potent antiproliferative activities and could be effective against different human cancer cells. Ethanolic extracts were prepared from Chelidonium majus, Myrica cerifera, Fumaria indica, Nigella sativa, and Silybum marianum, and the antiproliferative assay was performed in HepG2 and HeLa human cancer cell lines. All plants extract exhibited antiproliferative potential against studied cancer cell lines in the dose and time-dependent manner. Chelidonium majus and Silybum marianum have shown promising results against HepG2 and HeLa cells, respectively, followed by Myrica cerifera, Fumaria indica, and Nigella sativa. Results indicated that utilization of whole plant extract as anticancer compounds could be of great value in generating novel chemotherapeutic drugs.

In vitro cytotoxic potential of Solanum nigrum against human cancer cell lines.

Plants have natural products which use to possess antiproliferative potential against many cancers. In the present study, six isolated fractions (ethyl acetate, petroleum ether, chloroform, n-butanol, ethanol and aqueous) from Solanum nigrum were evaluated for their cytotoxic effect on different cell lines. Hepatic carcinoma cell line (HepG2), cervical cancer cell line (HeLa) and baby hamster kidney (BHK) used as normal non-cancerous cells were evaluated for cytotoxicity against isolated fractions. Cell viability assay was performed to evaluate the cytotoxicity of all fractions on different cell lines followed by the lactate dehydrogenase and vascular endothelial growth factor assays of most active fraction among all screened for cytotoxic analysis. HPLC analysis of most active fractions against cytotoxicity was performed to check the biological activity of compounds. Results displayed the potent cytotoxic activity of ethyl acetate fraction of S. nigrum against HepG2 cells with IC50 value of 7.89 µg/ml. Other fractions exhibited potent anticancer activity against HepG2 cells followed by HeLa cells. Fractions in our study showed no cytotoxicity in BHK cells. Cytotoxic activity observed in our current study exposed high antiproliferative potential and activity of ethyl acetate fraction against HepG2 cells. The results demonstrated that S. nigrum fractions exhibited anticancer activity against hepatic and cervical cancer cell lines with non-toxic effect in normal cells. These results reveal significant potential of S. nigrum for the therapeutic of cancers across the globe in future.

Safety and Efficacy of Suprachoroidal Injection of Triamcinolone in Treating Macular Edema Secondary to Noninfectious Uveitis.

Introduction  One of the leading causes of blindness throughout the world is uveitis, which predominantly results in the feared complication of macular edema. We report the safety and efficacy of suprachoroidal injection of triamcinolone acetonide in the treatment of macular edema secondary to noninfectious uveitis.  Methodology  This prospective, nonrandomized interventional study was conducted at Layton Rahmatullah Benevolent Trust (LRBT) Eye Hospital, Lahore, from August 2019 till July 2020. All individuals older than 18 years, nonpregnant females with a central macular thickness of >320 µm were included. Those patients with uncontrolled diabetes, immunodeficiency, or any other disease mandating systemic corticosteroid use were excluded. All patients had a detailed ocular exam one week before the treatment, and 0.1 ml of triamcinolone acetonide 40 mg/ml was injected using a 30-G hollow needle into the suprachoroidal space. After the injection, an eye patch was applied and the patient was observed for three hours. All data were documented in a preformed proforma.  Results A total of 30 patients were included in the study with a mean age of 38.1 ± 9.48 years. Statistically significant differences were found between central macular thickness at presentation and at one and three months of the procedure, i.e., 569.60 ± 170.396, 266.77 ± 73.127, and 208.27 ± 37.292 µm, respectively. A similar difference was observed when comparing visual acuity at baseline to visual acuity at one and three months of the procedure (p < 0.001).  Conclusion  The current study indicates that a single dose of suprachoroidal injection of triamcinolone acetonide for the treatment of macular edema secondary to uveitis is safe and efficacious. No rise in intraocular pressure (IOP) was observed during the study period. Significant improvements in central macular thickness and visual acuity as well as tolerability and safety of the treatment were seen in our study. Further larger-scale studies are needed to ascertain the long-term benefits of the suprachoroidal triamcinolone acetonide.

Serum hepcidin response as a marker of iron deficiency during second trimester of pregnancy: A multicenter cohort study in Lahore.

Iron deficiency diagnosis is a key health priority during pregnancy. The precise determination of indicators is needed for the evaluation of iron deficiency. In the present study, we investigated the diagnostic features of hepcidin concentration as an iron deficiency assay during the second trimester of pregnancy. We collected 401 venous blood samples of pregnant females from 4 separate birthing hospitals. All the females were within 13-26 weeks of their pregnancy and without any comorbid conditions. The complete blood count, total iron binding capacity, ferritin, serum iron and serum hepcidin were determined. The women were categorized as being non-iron deficient (N-ID), iron deficient (ID), or with iron deficiency anemia (IDA). The mean hepcidin values for examined groups were, i.e., non-iron deficiency was 31.45±4.70 (µg/L), iron deficiency 20.47±2.48 (µg/L) and iron deficiency anemia was 17.33±1.90 (µg/L). The N-ID's hemoglobin mean levels were 13.05±0.10g/dL, ID 12.66±0.05g/dL and the IDA 8.11±00.12g/dL. In this article variations in hepcidin levels between N-ID, ID and IDA women are uncovered and it is reported that the lower hepcidin levels diagnosed in IDA are closely linked to hemoglobin in Pakistani women. Hence it is concluded that hepcidin can be a valuable marker in identifying iron deficiency and iron deficiency anemia during the second trimester of pregnancy, according to the Pearson's correlation data.

A Novel Homozygous Frameshift Variant in DYM Causing Dyggve-Melchior-Clausen Syndrome in Pakistani Patients.

Background: Dyggve-Melchior-Clausen syndrome (DMC) is a skeletal dysplasia with associated defects of brain development and intelligence. The truncating pathogenic variants in DYM are the most frequent cause of DMC. Smith-McCort (SMC), another skeletal dysplasia, is also caused by non-synonymous DYM variants. Methods and Results: In the current study, we examined a Pakistani consanguineous family with three affected members. Clinical features like spondyloepimetaphyseal dysplasia, indicative of characteristic skeletal abnormalities, and intellectual disability were observed. Our male patients had microcephaly and coarse facial features while the female patient did not represent microcephaly or abnormal facies, which are significant features of DMC patients. Sanger sequencing identified a novel homozygous frameshift insertion (c.95_96insT, p.W33Lfs*14) in DYM, which likely leads to nonsense-mediated decay (NMD). Conclusion: The novel frameshift change verifies the fact that pathogenic variants in DYM are the most frequent cause of DMC.

Multiple Risk Factors: A Challenge in the Management of Autism.

Autism Spectrum Disorder (ASD) is an emerging health problem involving 1 out of every 68 children. The incidence rate of autism has increased 3 folds during the last 3 decades. Due to the illusive picture of aetiology, a considerable number of autistic children fail to receive proper behavioural and medicational treatment. The present study provides a cumulative account of autism risk factors. Several factors including the gene expression and gene mutations, environmental pollution, metal ion accumulation, exposure to pesticides, immune deficiencies, viral infections, mother's age, health, mental status, mother's interactions with the foetus, vaccination of mother and children, and modulations in gut microbiota have been debated. These risk factors may contribute to the development of autism either independently or synergistically leading to a broad spectrum of characteristics observed in autistic patients. The variable quantitative influence of a wide spectrum of risk factors may result in a unique set of features in each autistic individual. However, the exact mechanism behind the combined impact of various aetiological factors is poorly understood hindering the adaptation of specified and effective therapies.