Solid Phase Synthesis, DFT Calculations, Molecular Docking, and Biological Studies of Symmetrical N 2,N 4,N 6-Trisubstituted-1,3,5-triazines.

A diversity-oriented, multicomponent convergent synthesis of symmetrical triazines through a one-pot protocol is presented in this research project. The assembly of trisubstituted triazines was initially carried out using easily available reagents through three different protocols, i.e., conventional, MW-assisted synthesis, and solid-supported MW-assisted synthesis using organic and inorganic support to carry out a comparative analysis as to which procedure best corresponds to a greener synthesis protocol. The compounds formed were characterized for structure elucidation and subjected to in vitro anticancer and antibacterial screening. Additionally, computational studies, such as DFT calculations and molecular docking analyses, were conducted.

Resolving residual acetabular dysplasia following successful brace treatment for developmental dysplasia of the hip in infants.

Aims: Radiological residual acetabular dysplasia (RAD) has been reported in up to 30% of children who had successful brace treatment of infant developmental dysplasia of the hip (DDH). Predicting those who will resolve and those who may need corrective surgery is important to optimize follow-up protocols. In this study we have aimed to identify the prevalence and predictors of RAD at two years and five years post-bracing. Methods: This was a single-centre, prospective longitudinal cohort study of infants with DDH managed using a published, standardized Pavlik harness protocol between January 2012 and December 2016. RAD was measured at two years' mean follow-up using acetabular index-lateral edge (AI-L) and acetabular index-sourcil (AI-S), and at five years using AI-L, AI-S, centre-edge angle (CEA), and acetabular depth ratio (ADR). Each hip was classified based on published normative values for normal, borderline (1 to 2 standard deviations (SDs)), or dysplastic (> 2 SDs) based on sex, age, and laterality. Results: Of 202 infants who completed the protocol, 181 (90%) had two and five years' follow-up radiographs. At two years, in 304 initially pathological hips, the prevalence of RAD (dysplastic) was 10% and RAD (borderline) was 30%. At five years, RAD (dysplastic) decreased to 1% to 3% and RAD (borderline) decreased to < 1% to 2%. On logistic regression, no variables were predictive of RAD at two years. Only AI-L at two years was predictive of RAD at five years (p < 0.001). If both hips were normal at two years' follow-up (n = 96), all remained normal at five years. In those with bilateral borderline hips at two years (n = 21), only two were borderline at five years, none were dysplastic. In those with either borderline-dysplastic or bilateral dysplasia at two years (n = 26), three (12%) were dysplastic at five years. Conclusion: The majority of patients with RAD at two years post-brace treatment, spontaneously resolved by five years. Therefore, children with normal radiographs at two years post-brace treatment can be discharged. Targeted follow-up for those with abnormal AI-L at two years will identify the few who may benefit from surgical correction at five years' follow-up.

Cosine and cotangent similarity measures for intuitionistic fuzzy hypersoft sets with application in MADM problem.

Intuitionistic fuzzy hypersoft sets (IFHSSs) are a novel model that is projected to address the limitations of Intuitionistic fuzzy soft sets (IFSSs) regarding the entitlement of a multi-argument domain for the approximation of parameters under consideration. It is more flexible and reliable as it considers the further classification of parameters into their relevant parametric valued sets. In this paper, we proposed some trigonometric (cosine and cotangent) similarity measures and their weighted trigonometric similarity measures (SMs). Trigonometric Similarity measures (SMs) for intuitionistic fuzzy hypersoft sets (IFHSSs) are significantly implied to check the similarity measures and help to determine the similarity between different factors. Also, in order to evaluate the validity of the significant study and apply the results to a daily life problem. We use them to solve problems involving the selection of renewable energy sources. According to several technical contributing factors, the analysis identifies the ideal location for the implementation of the energy production units. Future case studies with many features and additional bifurcation along with multiple decision-makers can use the suggested methodologies. Also, several existing structures, such as fuzzy, Pythagorean fuzzy, Neutrosophic theories, etc., can be utilized with the suggested method.

Unveiling the Antibiotic Susceptibility and Antimicrobial Potential of Bacteria from Human Breast Milk of Pakistani Women: An Exploratory Study.

Background: Human life quality and expectancy have increased dramatically over the past 5 decades because of improvements in nutrition and antibiotic's usage fighting against infectious diseases. Yet, it was soon revealed that the microbes adapted to develop resistance to any of the drugs that were used. Recently, there is great concern that commensal bacteria from food and the gastrointestinal tract of humans and animals could act as a reservoir for antibiotic resistance genes. Methodology. This study was intended for evaluating the phenotypic antibiotic resistance/sensitivity profiles of probiotic bacteria from human breast milk and evaluating the inhibitory effect of the probiotic bacteria against both Gram-negative and Gram-positive bacteria. Results: The results point out that some of the isolated bacteria were resistant to diverse antibiotics including gentamycin, imipenem, trimethoprim sulfamethoxazole, and nalidixic acid. Susceptibility profile to certain antibiotics like vancomycin, tetracycline, ofloxacin, chloramphenicol, streptomycin, rifampicin, and bacitracin was also observed. The antimicrobial qualities of cell-free supernatants of some probiotic bacteria inhibited the growth of indicator bacteria. Also, antimicrobial properties of the probiotic bacteria from the present study attributed to the production of organic acid, bacterial adhesion to hydrocarbons (BATH), salt aggregation, coaggregation with pathogens, and bacteriocin production. Some isolated bacteria from human milk displayed higher hydrophobicity in addition to intrinsic probiotic properties like Gram-positive classification, catalase-negative activity, resistance to gastric juice (pH 2), and bile salt (0.3%) concentration. Conclusion: This study has added to the data of the antibiotic and antimicrobial activity of some probiotic bacteria from some samples of Pakistani women breast milk. Probiotic bacteria are usually considered to decrease gastrointestinal tract diseases by adhering to the gut epithelial and reducing population of pathogens and in the case of Streptococcus lactarius MB622 and Streptococcus salivarius MB620 in terms of hydrophobicity and exclusion of indicator pathogenic strains.

Isolation and Characterization of Lactobacillus crispatus, Lactococcus lactis, and Carnobacterium divergens as Potential Probiotic Bacteria from Fermented Black and Green Olives (Olea europaea): An Exploratory Study.

Background: Table olives are becoming well recognized as a source of probiotic bacteria that might be used to create a health-promoting fermented food product by traditional procedures based on the activities of indigenous microbial consortia present in local environments. Methodology. In the present study, the characterization of probiotic bacteria isolated from mince, chunks, and brine of fermented green and black olives (Olea europaea) was done based on morphological, biochemical, and physiological characteristics. Results: Bacterial isolates demonstrated excellent survival abilities at 25, 37, and 45°C and at a variable range of pH. However, the optimum temperature is 37 and the optimum pH is 7 for all three isolates. An antimicrobial susceptibility pattern was found among these isolates through the disc diffusion method. Most of the isolates were susceptible to streptomycin, imipenem, and chloramphenicol, whereas, amoxicillin showed resistance to these isolates, and variable results were recorded for the rest of the antibiotics tested. The growth of the isolates was optimum with the supplementation of 3% NaCl and 0.3% bile salt. The isolated bacteria were able to ferment skimmed milk into yogurt, hence making it capable of producing organic acid. Conclusion: Isolates of Lactobacillus crispatus MB417, Lactococcus lactis MB418 from black olives, and Carnobacterium divergens MB421 from green olives were characterized as potential candidates for use as starter cultures to induce fermentation of other probiotic food products.

Targeting the tumor microenvironment: Potential strategy for cancer therapeutics.

Cellular and stromal components including tumor cells, immune cells, mesenchymal cells, cancer-linked fibroblasts, and extracellular matrix, constituent tumor microenvironment (TME). TME plays a crucial role in reprogramming tumor initiation, uncontrolled proliferation, invasion and metastasis as well as response to therapeutic modalities. In recent years targeting the TME has developed as a potential strategy for treatment of cancer because of its life-threatening functions in restricting tumor development and modulating responses to standard-of-care medicines. Cold atmospheric plasma, oncolytic viral therapy, bacterial therapy, nano-vaccine, and repurposed pharmaceuticals with combination therapy, antiangiogenic drugs, and immunotherapies are among the most effective therapies directed by TME that have either been clinically authorized or are currently being studied. This article discusses above-mentioned therapies in light of targeting TME. We also cover problems related to the TME-targeted therapies, as well as future insights and practical uses in this rapidly growing field.

Streptococcus lactarius MB622 and Streptococcus salivarius MB620 isolated from human milk reduce chemokine IL-8 production in response to TNF-α in Caco-2 cell line, an exploratory study.

Streptococci are a predominant genera of the human milk microbiome. Among different lactic acid bacteria (LAB) a few Streptococcal strains are also considered as probiotics. Probiotic bacteria are reported to modulate immunity when consumed in adequate amount and bacterial hydrophobicity can be considered as a preliminary experiment for the adhesive capability of probiotic bacteria to the epithelial cells. The present study aimed to investigate the probiotic, hydrophobic and immune modulation property of Streptococcus lactarius MB622 and Streptococcus salivarius MB620, isolated from human milk. S. lactarius MB622 and S. salivarius MB620 displayed higher hydrophobicity (78 % and 59 % respectively) in addition to intrinsic probiotic properties such as gram positive classification, catalase negative activity, resistance to artificially stimulated gastric juice and gastrointestinal bile salt concentration. In conclusion Streptococcus lactarius MB622 and Streptococcus salivarius MB620 isolated from human milk when administered in sufficient amount and for certain duration could be used to reduce inflammation inside the colon by reducing the production of inflammatory booster (IL-8) in diseased state.

Promise of dostarlimab in cancer therapy: Advancements and cross-talk considerations.

In recent years, immunotherapy for cancer treatment using monoclonal antibodies has shown clinical success, particularly with programmed cell death protein 1 (PD-1) and its ligand programmed death-ligand 1 (PD-L1). Dostarlimab, an immune checkpoint inhibitor, interacts with adaptive immunity by binding to human PD-1, inhibiting PD-L1 and PD-L2 interactions, and cross-talk with adaptive immunity. Recent clinical trials have shown that dostarlimab is effective in treating mismatch repair deficiency (dMMR) in endometrial cancer patients, leading to its approval in the United States and the European Union in 2021. This article provides a comprehensive overview of dostarlimab, its therapeutic ability, and the different indications for which it is being used. Dostarlimab could serve as a potential alternative to many cancer treatments that frequently have severe consequences on patients' quality of life.

Antimicrobial activity of comfort related properties of silk treated with herbal extracts in making of reusable masks

The study was aimed at divulging an eco-friendly antimicrobial finish on 100 % silk woven fabric. The leaves' extract of Azadirachata indica, Butea monosperma and Litche chinensis were used as the development of eco-friendly antimicrobial finish. The antimicrobial property and comfort related property were checked before and after applying antimicrobial finish. In comfort related property absorbency & air permeability were checked. The ASTEM E2149 Shake Flask method was used to check antimicrobial finish and AATCC method was used for checking fabric property. One way ANOVA statistical test was applied for analysis of results. The FTIR and SEM results showed the presences of finish on fabrics. In comfort related property, absorbency and air permeability was increased. The results showed that antimicrobial finish made 100% reduction against microorganism up to 25 washes which can be used in making reusable masks fight against COVID- 19.

Association of maternal nutritional status with neonatal anthropometry: A cross-sectional study.

OBJECTIVE: To identify the association of maternal nutritional status with neonatal anthropometry. METHODS: The multi-centre, cross-sectional survey was conducted at two government and 5 private hospitals in Lahore, Pakistan, from July 2016 to August 2017, and comprised mothers and their neonates. A semi-structured self-administered questionnaire was used along with data from patient files. Maternal nutritional status was assessed through biochemical profile. Standard procedures and safety measures were employed during data collection of neonatal anthropometric measurements. Data was analysed using SPSS 22. RESULTS: Of the 800 subjects, 407(50.9%) were from government hospitals and 393(49.1%) from private hospitals. The mean maternal age was 27.72+14.42 years. Among the neonates, 365(45.6%) were girls and 435(54.4%) were boys. Significantly lower anthropometric measurements were noted in mothers with poor haemoglobin, haematocrit, red blood cell, fasting glucose levels as well as those with higher uric acid, and lower serum albumin, total protein, and in those with blood in urine (p<0.05). CONCLUSIONS: Maternal biochemical markers were found to be critical in evaluating mothers at risk of delivering neonates with low anthropometric measurements.

Novel epigenetic therapeutic strategies and targets in cancer.

The critical role of dysregulated epigenetic pathways in cancer genesis, development, and therapy has typically been established as a result of scientific and technical innovations in next generation sequencing. RNA interference, histone modification, DNA methylation and chromatin remodelling are epigenetic processes that control gene expression without causing mutations in the DNA. Although epigenetic abnormalities are thought to be a symptom of cell tumorigenesis and malignant events that impact tumor growth and drug resistance, physicians believe that related processes might be a key therapeutic target for cancer treatment and prevention due to the reversible nature of these processes. A plethora of novel strategies for addressing epigenetics in cancer therapy for immuno-oncological complications are currently available - ranging from basic treatment to epigenetic editing. - and they will be the subject of this comprehensive review. In this review, we cover most of the advancements made in the field of targeting epigenetics with special emphasis on microbiology, plasma science, biophysics, pharmacology, molecular biology, phytochemistry, and nanoscience.

Global burden of the COVID-19 associated patient-related delay in emergency healthcare: a panel of systematic review and meta-analyses.

BACKGROUND: Apart from infecting a large number of people around the world and causing the death of many people, the COVID-19 pandemic seems to have changed the healthcare processes of other diseases by changing the allocation of health resources and changing people's access or intention to healthcare systems. OBJECTIVE: To compare the incidence of endpoints marking delayed healthcare seeking in medical emergencies, before and during the pandemic. METHODS: Based on a PICO model, medical emergency conditions that need timely intervention was selected to be evaluated as separate panels. In a systematic literature review, PubMed was quarried for each panel for studies comparing the incidence of various medical emergencies before and during the COVID-19 pandemic. Markers of failure/disruption of treatment due to delayed referral were included in the meta-analysis for each panel. RESULT: There was a statistically significant increased pooled median time of symptom onset to admission of the acute coronary syndrome (ACS) patients; an increased rate of vasospasm of aneurismal subarachnoid hemorrhage; and perforation rate in acute appendicitis; diabetic ketoacidosis presentation rate among Type 1 Diabetes Mellitus patients; and rate of orchiectomy among testicular torsion patients in comparison of pre-COVID-19 with COVID-19 cohorts; while there were no significant changes in the event rate of ruptured ectopic pregnancy and median time of symptom onset to admission in the cerebrovascular accident (CVA) patients. CONCLUSIONS: COVID-19 has largely disrupted the referral of patients for emergency medical care and patient-related delayed care should be addressed as a major health threat.

Novel therapeutic drug strategies to tackle immune-oncological challenges faced by cancer patients during COVID-19.

INTRODUCTION: For the clinical treatment of cancer patients, coronavirus (SARS-CoV-2) can cause serious immune-related problems. Cancer patients, who experience immunosuppression due to the pathogenesis and severity of disease, may become more aggressive due to multiple factors such as age, comorbidities, and immunosuppression. In this pandemic era, COVID-19 causes lymphopenia, cancer cell awakening, inflammatory diseases, and a cytokine storm that worsens disease-related morbidity and prognosis. AREAS COVERED: We discuss all the risk factors of COVID-19 associated with cancer patients and propose new strategies to use antiviral and anticancer drugs for therapeutic purposes. We bring new drugs, cancers and COVID-19 treatment strategies together to address the immune system challenges faced by oncologists. EXPERT OPINION: The chronic inflammatory microenvironment caused by COVID-19 awakens dormant cancer cells through inflammation and autoimmune activation. Drug-related strategies to ensure that clinical treatment can reduce the susceptibility of cancer patients to COVID-19, and possible counter-measures to minimize the harm caused by the COVID-19 have been outlined. The response to the pandemic and recovery has been elaborated, which can provide information for long-term cancer treatment and speed up the optimization process.

Effect of antenatal depression on maternal dietary intake and neonatal outcome: a prospective cohort.

BACKGROUND: In Pakistan, incidence of antenatal depression ranges from 18 to 80 %, which goes undiagnosed, resulting in maternal and neonatal implications. The current study aimed to examine the association of antenatal depression with maternal dietary intake and neonatal outcome. METHODS: A hospital-based, prospective cohort study was conducted on 94 middle class antenatal attendees coming to a tertiary care hospital in Lahore, Pakistan at the beginning of second trimester. Participants fulfilling eligibility were enrolled consecutively after taking written informed consent. Exposure group was identified by Edinburgh Postnatal Depression Scale (EPDS) and cohort members were followed till after delivery. Maternal dietary intake was assessed by 24-h Recall and Food Frequency Checklist, while neonatal outcome was identified through patient files before discharge. Data on potential confounders was collected. Loss to follow up was 13 % (82/94). Data was collected from April-September 2013. Results for 82 participants were analyzed using SPSS version 21. RESULTS: EPDS screened 35/82 (43 %) eligible antenatal attendees as depressed, out of which 16/35 (20 %) were severely depressed and 19/35 (23 %) were moderately depressed. Incidence of poor maternal dietary intake was more in females with antenatal depression. Antenatal depression increased the risk of poor Healthy Eating Index (RR = 2.58, C.I 1.60-5.23, AR = 62 %), carbohydrate <175 gm (RR = 1.188, CI 0.836-1.688, AR = 15 %), protein <71 gm (RR = 1.343, CI 1.059-1.703, AR = 26 %) and fat <55 gm (RR = 2.954, CI 1.612-5.416, AR = 67 %) Incidence of neonatal outcomes included, Fetal Growth Retardation (RR = 2.70, C.I 0.69-3.70, AR = 60 %), preterm birth (RR = 1.60, C.I 0.72-2.45, AR = 54 %), low Apgar score (RR = 2.70, C.I 0.69-3.70, AR = 60 %) and Low Birth Weight (RR = 0.56, C.I 0.93-1.39, AR = -44 %). CONCLUSION: Antenatal women with depression developed poor dietary intake and had increased incidence of Fetal Growth Retardation, preterm birth and low Apgar score, but not of Low Birth Weight.

Production and Biomedical Applications of Probiotic Biosurfactants.

Biosurfactants have been widely used for environmental and industrial applications. However, their use in medical field is still limited. Probiotic biosurfactants possess an immense antimicrobial, anti-adhesive, antitumor, and antibiofilm potential. Moreover, they have an additional advantage over conventional microbial surfactants because probiotics are an integral part of normal human microflora and their biosurfactants are innocuous to human. So, they can be effectively exploited for medicinal use. Present review is aimed to discourse the production and biomedical applications of probiotic biosurfactants.

Use of external fixators for damage-control orthopaedics in natural disasters like the 2005 Pakistan earthquake.

PURPOSE: In the 2005 Pakistan earthquake, the great many injured with multiple fractures and open wounds provided a unique opportunity to practice damage-control orthopaedics. External fixators remain a time-tested tools for operating surgeons on such occasions. The locally manufactured, readily available Naseer-Awais (NA) external fixator filled such needs of this disaster with good outcome. METHODS: This is a retrospective descriptive study of 19,700 patients that presented over seven months to the two centres established by the lead author (SMA) in Muzaffarabad and Mansehra just one night after the 2005 earthquake. A series of local and foreign orthopaedic surgeon teams operated in succession. The computerised patient data collection of 1,145 operations was retrospectively analysed. RESULTS: Of the 19,700 patients presenting to the SMA centres, 50% had limb injuries. Total fracture fixations were 1,145, of which 295 were external fixations: 185 were applied on the lower limb and 90 on upper limb, the majority were applied on tibia. CONCLUSION: External fixators are valuable damage-control tools in natural disasters and warfare injuries. The locally manufactured NA external fixator served the needs of the many limb injuries during the 2005 Pakistan earthquake.

Outcome of neurolysis combined with anterior submuscular transfer of ulnar nerve in McGowan Grade II and III tardy ulnar nerve palsy.

OBJECTIVE: To see the impact of combined neurolysis and submuscular transposition approach in patients with tardy ulnar nerve palsy of Mc Gowan grades II and III. METHODS: The descriptive case series was conducted at King Edward Medical University, Mayo Hospital, Lahore, between January 2013 and January 2014, and comprised patients with positive nerve conduction study and electromyography, aged above 14 years with McGowan grades II and III tardy ulnar nerve palsy of any aetiology. They were treated by a single surgeon and his team. Anterior submuscular transposition with internal neurolysis under loupes was performed. Improvement in hand function was determined with Quick Disabilities of the Arm, Shoulder and Handscore 6 months postoperatively. Data was analysed using SPSS 16. RESULTS: Of the 20 consecutive patients in the study, 14(70%) were males and 6(30%) were females with a standard deviation of 16.35(range: 14-60 years). Six-month postoperatively, Quick Disabilities of the Arm, Shoulder and Handscore had a mean improvement from 43 to 21 (standard deviation from 6.46 to 7.51) supporting the evidence that 18(90%) patients had significant improvement in hand function. There was 1(5%) excellent, 13(65%) good, 4(20%) fair and 2(10%) poor functional outcomes. CONCLUSIONS: Patients with Mc Gowan grades II and III tardy ulnar nerve palsy showed good functional outcome when internal neurolysis was combined with submuscular transposition.

Study of the severity of musculoskeletal injuries and triage during the 2005 Pakistan earthquake.

PURPOSE: On 8 October 2005 a massive earthquake hit the northern mountainous areas of Pakistan and Kashmir causing 73,338 deaths and leaving over 125,000 severely injured. In a region which was less prepared for such an enormous disaster, mobilising rescue, relief and rehabilitation posed great challenges. The first author (SMA) established two level 1 orthopaedic trauma and rehabilitation units in each of two severely hit major cities through private philanthropy. According to the severity of injuries, the patients were triaged and treated. The aim of this study is to improve the future strategies in similar scenarios. METHODS: This is a retrospective review of medical records of patients suffering from musculoskeletal injuries in the aftermath of the 2005 earthquake who were managed in these centres in the order of triage priority. The patients were received, categorised, worked up and provided definitive surgical procedures. All patients were provided assistance for the fitting of a prosthesis and rehabilitation. RESULTS: Of 128,304 (total of injured patients), 19,700 were managed in two centres established by SMA during the first months after the earthquake. Of these, 112 patients underwent amputations of upper and lower limbs. CONCLUSIONS: In a massive calamity over a wide geographical area away from big university hospitals, such as the 2005 Pakistan earthquake, the level 1 operating theatre facilities must be established within the area to meet the immediate needs of the patients nearest to their homes and families, and run forever so that patients can have excellent follow-up and can use the same facilities regularly. In the aftermath of this earthquake the need to practise triage in the first 72 hours was thoroughly realised and effectively practised in our centres.

Amputations of limbs during the 2005 earthquake in Pakistan: a firsthand experience of the author.

PURPOSE: On 8 October 2005 a massive earthquake hit the northern mountainous areas of Pakistan and Kashmir causing 73,338 deaths and leaving over 125,000 severely injured. In a region which was less prepared for such an enormous disaster, mobilising rescue, relief and rehabilitation posed great challenges. The lead author (SMA) established two level 1 orthopaedic trauma and rehabilitation units in existing public hospitals through private philanthropy in the earthquake struck cities of Muzaffarabad in Kashmir and Mansehra in Khyber Pakhtun Khuwa (KPK) Province. The purpose was to combat the major catastrophe and later study the pattern of injuries especially amputations so as to improve the future strategies in similar scenarios. METHODS: This is a retrospective descriptive study of patients suffering from injuries of the limbs due to the earthquake who were managed in these centres with special emphasis on the patients with amputated limbs. The patients were received, worked up, investigated and prepared for definitive surgical procedures, in this case amputations. All patients were provided assistance for the fitting of a prosthesis and rehabilitation by referring them to specialised centres. RESULTS: Of 128,304 patients, 19,700 were managed in the centres established by the lead author over a period of seven months. Of these, 112 patients underwent amputations of upper and lower limbs. CONCLUSIONS: In a massive calamity over a wide geographic area away from big university hospitals, such as the 2005 Pakistan earthquake, the level 1 operating theatre facilities must be established within the area to meet the needs of the patients nearest to their homes and families, and run forever so that patients can have excellent follow-up and can use the same facilities regularly. For example, in this study we managed 112 amputees and placed them in a rehabilitation programme, and transferred these centres to the hospital authorities after five years.

Neuroendocrine carcinoma of breast.

Neuroendocrine tumours (NETS) are rare tumours. The commonest site of occurrence is the gastrointestinal tract. NETS in the breast are even rarer, accounting for less than 0.1% of all breast cancers and less than 1% of all NETS. We are reporting a case of primary neuroendocrine carcinoma of the breast in a 60 years old female. Investigations were done to rule out any other associated lesion. Patient was treated by modified radical mastectomy and adjuvant chemo and radiotherapy.