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Hamid Ehsan,1 Ahsan Wahab,2 Muhammad Ammar Shafqat,3 Muhammad Khawar Sana,4 Farhan Khalid,4 Syed Maaz Abdullah,4 Ali Jaan,4 Muhammad M Sheikh,5 Ahmad Muneeb,5 Sajid Ehsan,6 Ali Younas Khan,7 Raheel Iftikhar,8 Faiz Anwer9 1Biohazardous Threat Agents and Emerging Infectious Diseases, Georgetown University, Washington, DC, USA; 2University of Alabama at Birmingham, Birmingham, AL, USA; 3Department of Internal Medicine, Pakistan Kidney and Liver Institute and Research Center, Lahore, Pakistan; 4Department of Internal Medicine, King Edward Medical University, Lahore, Pakistan; 5Department of Internal Medicine, Faisalabad Medical University, Faisalabad, Pakistan; 6Department of Internal Medicine, Anne Arundel Medical Center, Annapolis, MD, USA; 7Department of Internal Medicine, St. Joseph Mercy Hospital, Oakland, Pontiac, MI, USA; 8Department of Hematology/Oncology, Armed Forces Bone Marrow Transplant Center/NIBMT, Rawalpindi, Pakistan; 9Department of Hematology/Oncology, Cleveland Clinic, Taussig Cancer Center, Hematology-Oncology, BMT, Cleveland, OH, USACorrespondence: Hamid EhsanMD, FACP MUMH, Department of Medicine, 201 E. University Parkway, Baltimore 21218, USATel +19172875423Fax +14105542184Email he150@georgeotown.eduAbstract: The blood transfusion (BT) system in Pakistan is fragmented, demand-driven and depends on weakly regulated transfusion practices. There is a considerable possibility that transfusion-transmissible infections (TTIs) are contributing to the current epidemic of hepatitis B virus (HBV) and hepatitis C virus (HCV) (affecting 7.4% of the general population) in the country. To study this issue, we conducted a systematic review to identify articles related to TTIs and transfusion safety in Pakistan from January 1, 2010 to January 31, 2020. A review of 33 articles met the final criteria for qualitative synthesis. Analysis of these studies showed a cumulative frequency of HBV 2.04%, HCV 2.44%, HIV 0.038%, syphilis 1.1% and malaria 0.11%. The frequency of coinfections among blood donors varied from 0.0099% to 0.35%. The highest number of coinfections were HCV and syphilis, followed by HCV and HBV infections. Syphilis and malaria were tested in only 38% and 46% of all the blood donations in one study. The rate of voluntary non-remunerated donations (VNRDs) was less than 13%, and male donors were 95% to 100% in these studies. There was a significant difference in the frequency of HBV and HCV in VNRDs (0.48%) as compared to replacement donors (RDs) (4.15%). In short, this review shows a high frequency of TTIs, especially HBV, HCV and syphilis in the blood donor population in Pakistan. There is a high dependency on RDs, minimal use of healthy voluntary blood donation practices, inadequate screening of high-risk donors, repeated collections of the blood from RDs, poor quality of screening methods and limited knowledge of donor health. Without standardized safe transfusion practices, there will be an ongoing increase in transmission of TTIs, especially HBV, HCV, syphilis, and HIV leading to a significant adverse public health impact.Keywords: transfusion-transmitted infections, hepatitis B, hepatitis C, HIV, syphilis, malaria

Zohair Jamil Gazzaz,1 Rahila Iftikhar,2 Tahir Jameel,1 Mukhtiar Baig,3 Manal Abdulaziz Murad2 1Department of Internal Medicine, Faculty of Medicine, Rabigh, King Abdulaziz University, Jeddah, Saudi Arabia; 2Department of Family Medicine, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia; 3Department of Clinical Biochemistry, Faculty of Medicine, Rabigh, King Abdulaziz University, Jeddah, Saudi ArabiaCorrespondence: Rahila IftikharDepartment of Family Medicine, Faculty of Medicine, King Abdulaziz University, Jeddah 22431, Saudi ArabiaTel +13467541966Email rahila_iftikhar@hotmail.comPurpose: To find out the association of dyslipidemia and comorbidities with risk factors among type-2 diabetes mellitus (T2DM) patients attending King Abdulaziz University Hospital (KAUH) Jeddah, Saudi Arabia (SA).Patients and Methods: Three hundred and twenty-five T2DM patients were enrolled from the electronic record of the KAUH. The patients’ existing comorbidities and dyslipidemia correlation with demographic, clinical, and available laboratory data were sought. Statistical analysis was performed on SPSS-23.Results: Of the total 325 T2DM patients with a mean age of 60.13± 10.5 years [males 95 (29.23%) and females 230 (70.77%)] were included from the electronic record. Poor glycemic control was observed in 222 (68.31%) subjects (HbA1c > 7%), and 154 (47.39%) subjects had DM for more than ten years. Among our study subjects, 103 (31.69%) were hypertensive (HTN), 112 (34.46%) had ischemic heart disease (IHD), 45 (13.85%) were obese, 8(2.46%) had a stroke and 269 (82.77%) had dyslipidemia. Of the total 269 dyslipidemic patients,168 (62.45%) were on hypolipidemic treatment. On comparison of study variables according to dyslipidemia versus normal lipid levels, the lipid profile, including HDLc, LDLc, TC, and TG, revealed a highly significant difference (p-value < 0.001) whereas many variables were not significantly different. HBA1c, FBG, and RBG were significantly higher in dyslipidemic subjects. Logistic regression analysis of risk factors and comorbidities in our patients revealed that age 60– 69 years and 70– 79 years had a significant association with comorbidities. Similarly, logistic regression analysis of risk factors and dyslipidemia in our patients revealed no statistically significant association.Conclusion: Our results observed that the comorbidities were associated with increasing age and common comorbidities were HTN, IHD, dyslipidemia. Our study has highlighted the current trends in T2DM symptomatology and comorbidities. Efficient management and control by early screening and developing healthy lifestyles in our patients can be very helpful in the prevention of all these highly morbid complications of this preventable disease.Keywords: dyslipidemia, DM, IHD, cholesterol, comorbidities, HbA1c, hypertension

Rahila Iftikhar, Bahaa Abdulrahman Aba Al Khail Family and Community Medicine Department, King Abdulaziz University Hospital, Jeddah, Saudi Arabia Background: Oral contraceptive pills (OCPs) are one of the most reliable methods of contraception. However, lack of knowledge about oral contraceptive use and inconsistent pill-taking might result in decreased efficacy. The study reported here aimed to explore women’s knowledge about oral contraceptive use and assess the factors associated with knowledge about OCPs among users.Methods: This cross-sectional survey was conducted at King Abdulaziz University Hospital, Jeddah, Saudi Arabia between April and June 2014. We included married, non-pregnant women >18 years old who had used a combined 21-day OCP for at least 3 months prior to recruitment. A questionnaire was used to collect the participants’ demographic information. It also assessed their knowledge about OCPs. Data were entered into and analyzed using SPSS software.Results: A total of 357 women were recruited. Of these, 57.7% reported they knew what to do after missing one or two pills, but only 18.3% knew exactly what to do after missing more than two pills consecutively. Postgraduate women had a significantly higher knowledge score than illiterate women (P=0.002) and those who had completed at least primary education (P=0.001). Conversely, there was no difference in knowledge scores between Saudi and expatriate women (P=0.2). Monthly incomes (P=0.2) and mode of OCP selection (P=0.2) were also not significantly associated with knowledge scores.Conclusion: Women had poor knowledge about OCP use. Appropriate measures should be taken to educate women about proper oral contraceptive use. Keywords: oral contraception, oral contraceptive, Saudi Arabia, OCP

Rahila Iftikhar,1 Razaz Tawfiq,2 Salem Barabie2 1Department of Family and Community Medicine, 2General Practice Department, King Abdul Aziz University, Jeddah, Saudi Arabia Background and objectives: Abuse occurs in all workplaces, including the medical field. The aim of this study was to determine the prevalence of perceived abuse among medical students, the types of abuse experienced during medical training, the source of abuse, and the perceived barriers to reporting abuse. Method: This cross-sectional survey was conducted between September 2013 and January 2014 among medical graduates of King Abdul Aziz University, Jeddah. The survey questionnaire was designed to gather information regarding the frequency with which participants perceived themselves to have experienced abuse, the type of abuse, the source of abuse, and the reasons for nonreporting of perceived abuse. Data were analyzed using the Statistical Package for the Social Sciences. Result: Of the 186 students enrolled in this study, 169 (90.9%) reported perceiving some form of abuse during medical school training. Perceived abuse was most often verbal (86.6%), although academic abuse (73.1%), sex discrimination (38.7%), racial or ethnic discrimination (29.0%), physical abuse (18.8%), religious discrimination (15.1%), and sexual harassment (8.6%) were also reported. Professors were most often cited as the sources of perceived abuse, followed by associate professors, demonstrators (or assistant teaching staff), and assistant professors. The Internal Medicine Department was the most frequently cited department where students perceived themselves to have experienced abuse. Only 14.8% of the students reported the abuse to a third party. Conclusion: The self-reported prevalence of medical student abuse at King Abdul Aziz University is high. A proper system for reporting abuse and for supporting victims of abuse should be set up, to promote a good learning environment. Keywords: maltreatment, medical school, mistreatment

Background: Hepatitis C is a major global health problem, with a high disease burden in developing countries like Pakistan. Rural communities in Pakistan have limited awareness about hepatitis C transmission, prevention, and control. This study aimed to assess knowledge and practices related to hepatitis C among patients in the rural community of Lasi Goth, Gadap Town, Karachi. Material and Method: A quantitative cross-sectional survey was conducted among 150 adult patients (>18 years) with known hepatitis C infection in Lasi Goth. Data was collected through face-to-face interviews using a structured questionnaire. The questionnaire captured socio-demographic information, knowledge about hepatitis C (causative agent, symptoms, transmission), attitudes towards its prevention, and related practices. Descriptive statistics were used to analyze the data. Results: Of 150 participants, 55% were males and mean age was 25 years. Majority (69.3%) had heard about hepatitis C, with main sources being television (28.7%) and other people (38.7%). Knowledge regarding hepatitis C was low, with less than half aware of the causative agent (42%) and symptoms (41.3%). Around 55% knew it spreads person-to-person, mainly by blood transmission (38%), shared razors/brushes (4.7%), injection drug use (12%), mother to child transmission (18.7%), and sexual contact (26.7%). Most (76%) believed hepatitis C was preventable through screening blood (20%), avoiding sharing razors/brushes (37.3%), and infected persons not donating blood (24.7%). Only 18% reported their families were involved in prevention efforts. A high proportion (88%) were using anti-hepatitis C drugs and 54.7% received hepatitis B vaccination. Conclusion: Patients from the rural community had limited knowledge about hepatitis C transmission routes and prevention measures. Culturally appropriate educational campaigns are required to raise awareness in rural communities regarding risks, prevention strategies, and control of hepatitis C infection.

Roadside unit (RSU) cloud and its vehicle-to-infrastructure (V2I) connectivity can enable various security, entertainment, and shared mobility applications for vehicles in intelligent transportation systems (ITS) through wireless communications. In this article, the deep programmability of software-defined networking (SDN) is employed to dynamically reconfigure network hosting services and their data forwarding information for effectively meeting the basic shared mobility applications’ needs in vehicle ad hoc networks (VANETs). Multipath is also enabled to forward data flow for balancing network links utilization rate and SDN is thus utilized to achieve the minimum cloud delay with the least number of hosts, which can be summarized as a mixed-integer linear programming (MILP) problem. The joint optimization (JO) algorithm is proposed and in contrast to the two single-objective algorithms which are the delay optimization (DO) algorithm and host optimization (HO) algorithm, respectively. Results show that, for the single-threading instance, the JO and DO algorithms are the same in essence. For the multithreading instance, the JO algorithm generally outperforms the two single-objective optimization algorithms, respectively, under given demands. Furthermore, results also demonstrate that the services should be deployed globally in a distributed manner rather than in the centralized manner for achieving the minimized cloud delay in designing an RSU cloud.

This paper investigates the response and characteristics of the narrowband power line communication (NB-PLC) technique for the effective control of electric appliances such as smart air conditioners (SACs) for demand side management (DSM) services. The expression for temperature sensitivity by examining the influence of atmospheric temperature variations on power consumption profile of all possible types of loads, i.e., residential, commercial, and industrial loads is derived and analyzed. Comprehensive field measurements on these power consumers are carried out in Lahore, Pakistan. The responses of low voltage channels, medium voltage channels, and transformer bridge for a 3–500 kHz NB-PLC frequency range are presented for DSM services. The master control room transmits control commands for the thermostat settings of SACs over power lines, crossing the transformer bridge to reach the SACs of power consumers by using communication protocol smart energy profile 1.0. The comparison of hourly and daily power consumption profiles under evaluation loads, by analyzing typical and variable frequency air conditioners on setting thermostat temperature at 25 °C and 27 °C conventionally and then by using DSM control technique, is analyzed. A prominent reduction in power consumption is found with the implementation of the DSM control technique.

Objective: To determine the incidence of respiratory viral infections in bone marrow transplant patients., Methods: The prospective, descriptive, cross-sectional study was conducted at a tertiary care hospital in Rawalpindi, Pakistan, from September 2019 to August 2020, and comprised respiratory specimens from recipients of haematopoietic stem cell transplant. The specimens were collected in viral transport medium, and were then taken to the Department of Virology. Multiplex polymerase chain reaction was performed on the specimens to ascertain the incidence and prevalence of respiratory viruses. Data was analysed using SPSS 24., Results: Of the 85 subjects, 53(62.35%) were males and 32(37.65%) were females. The overall median age was 20.0 years (interquartile range: 11.0-32.0 years). Respiratory viral infections were detected in 31(36.4%) specimens. Among them, human rhinovirus was detected in 12(38.7%) cases, respiratory syncytial virus in 5(16.1%), influenza A/H3 in 4(13%), human parainfluenza virus-1 in 3(9.7%), adenovirus in 2(6.4%), human parainfluenza virus-3 in 1(3.2%), human parainfluenza virus-4 in 1(3.2%) and human metapneumovirus in 1(3.2%) case. There were 2(6.4%) cases of co-infection., Conclusions: More than one-third recipients of haematopoietic stem cell transplant were found to have respiratory viral infections, highlighting the importance of employing multiplex respiratory polymerase chain reaction in early diagnosis and treatment of such infections.

Allogeneic hematopoietic cell transplantation (HCT) is a potentially curative treatment for severe aplastic anemia (SAA). Existing guidance about HCT in SAA is primarily derived from expert reviews, registry data and societal guidelines; however, transplant-specific guidelines for SAA are lacking. A panel of SAA experts, both pediatric and adult transplant physicians, developed consensus recommendations using Grading of Recommendation, Assessment, Development, and Evaluation (GRADE) methodology employing a GRADE guideline development tool. The panel agrees with previous recommendations for the preferential use of bone marrow as a graft source and the use of rabbit over horse antithymocyte globulin (ATG) for HCT conditioning. Fludarabine containing regimens are preferred for patients at high risk of graft failure and those receiving matched unrelated or haploidentical donor transplant. Given advancements in HCT, the panel does not endorse the historical 40-year age cut-off for considering upfront HCT in adults, acknowledging that fit older patients may also benefit from HCT. The panel also endorses increased utilization of HCT by prioritizing matched unrelated or haploidentical donor HCT over immunosuppressive therapy in children and adults who lack a matched related donor. Finally, the panel suggests either calcineurin inhibitor plus methotrexate or post-transplant cyclophosphamide-based graft-versus-host disease (GVHD) prophylaxis for matched related or matched unrelated donor recipients. These recommendations reflect a significant advancement in transplant strategies for SAA and highlight the importance of ongoing and further research to revisit current evidence in terms of donor choice, conditioning chemotherapy, GVHD prophylaxis and post-transplant immunosuppression., (Copyright © 2024 The American Society for Transplantation and Cellular Therapy. All rights reserved.)

Background & Aims: The obesity epidemic is associated with increased colon cancer progression. As lipid droplets (LDs) fuel tumor growth, we aimed to determine the significance of diacyltransferases (diacylglycerol o-acyltransferases 1 and 2 [DGAT1/2]), responsible for LD biogenesis, in obesity-mediated colonic tumorigenesis., Methods: Human colon cancer samples, colon cancer cells, colonospheres, and Apc Min/+ colon cancer mouse model on a high-fat diet were employed. For DGAT1/2 inhibition, enzymatic inhibitors and small interfering RNA were used. Expression, pathways, cell cycle, and growth were assessed. Bioinformatic analyses of CUT&RUN and RNA sequencing data were performed., Results: DGAT1/2 levels in human colon cancer tissue are significantly elevated with disease severity and obesity (vs normal). Their levels are increased in human colon cancer cells (vs nontransformed) and further enhanced by fatty acids prevalent in obesity; augmented DGAT2 expression is MYC-dependent. Inhibition of DGAT1/2 improves FOXO3 activity by attenuating PI3K, resulting in reduced MYC-dependent DGAT2 expression and accumulation of LDs, suggesting feedback. This inhibition attenuated growth in colon cancer cells and colonospheres via FOXO3/p27kip1 cell cycle arrest and reduced colonic tumors in Apc Min/+ mice on a high-fat diet. Transcriptomic analysis revealed that DGAT1/2 inhibition targeted metabolic and tumorigenic pathways in human colon cancer and colon cancer crypts, stratifying human colon cancer samples from normal. Further analysis revealed that this inhibition is predictive of advanced disease-free state and survival in patients with colon cancer., Conclusions: This is a novel mechanism of DGAT1/2-dependent metabolic and tumorigenic remodeling in obesity-facilitated colon cancer, providing a platform for future development of effective treatments for patients with colon cancer., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Hemophagocytic Lymphohistiocytosis (HLH) is a rare disorder of immune dysregulation characterized by fever, cytopenias, and splenomegaly. Its primary form poses a therapeutic challenge due to its high fatality when left untreated. We retrospectively analyzed 28 patients who underwent related-donor allogeneic stem cell transplant for primary HLH from 2010 to 2021. Among them were 10 cases of familial HLH, 8 cases of Griscelli syndrome type 2, and 1 case each with PRF1 and STX11 mutations. All the patients underwent transplants with reduced-intensity or myeloablative conditioning and 26 of them achieved neutrophil engraftment at a median of day + 14. The donors were either fully matched (68%) or haploidentical (32%). With a median follow-up of 1 year, overall survival was 68% (n = 19) and disease-free survival was 64.4% (n = 18). OS was better in patients transplanted with a sibling donor (compared to parent donor), who achieved complete donor chimerism, and those transplanted early in the course of the disease (diagnosis to transplant duration less than 6 months)., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: To determine the Pattern of immune reconstitution (IR) post allogeneic stem cell transplant at six months., Study Design: Prospective observational study. Place and duration of the study: This study was conducted at The Armed Forces Bone Marrow Transplant Centre (AFMBTC) Rawalpindi, Pakistan, from May 2022 to December 2022., Methodology: After approval from the institutional review board, informed/written consents were taken from patients. All patients (both genders, irrespective of age) undergoing allogeneic hematopoietic stem cell transplant were included in the study. Patients undergoing haplo-identical or autologous bone marrow transplants were excluded from the study. Innate immune reconstitution was checked by complete blood count and adaptive immune reconstitution at six months was checked lymphocyte subset analysis and serum immunoglobulin levels. Data was entered in pre-designed proforma and was analyzed using IBM Corp. Released 2017. IBM SPSS Statistics for Windows, Version 25.0. Armonk, NY: IBM Corp., Results: This study analyzes 43 patients, including 67% (n=29) males. The median age at the time of HSCT was 11.19 years. Cellular and humoral reconstitution at six months after transplant was used to assess immune reconstitution. Innate immune reconstitution was checked by complete blood count for count recovery (Neutrophil engraftment), and adaptive immune reconstitution (cellular/humoral) at six months was checked lymphocyte subset analysis and serum immunoglobulin levels. By using chi-square, significant associations were found as pre-transplant condition regimen with CD4 (PChi= 0.001), GVHD prophylaxis with CD4 (PChi= 0.04), source of stem cells with CD19 (PChi= 0.008), patient-donor gender disparity with CD19 (PChi= 0.05), GVHD treatment low CD19 (PChi= 0.04), patient-donor relationship with IgA(PChi= 0.007), IgG (PChi= 0.001), and IgM (PChi= 0.001), gender of the patient with IgA (PChi= 0.04)., Conclusion: Our data suggested that at post-transplant six months, there was adequate immune reconstitution except for CD4 and CD4:CD8 ratio. Therefore, post-transplant, six months in Allo-HSCT could be considered for immunization., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Armed Forces Bone Marrow Transplant Centre Rawalpindi Pakistan issued approval IRB-012/AFBMTC/Approval/2022. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Rahim et al.)

Within the family Fabaceae , the genus Glycine is composed of two subgenera annuals (2n=40) and perennials. This life strategy transition may have differentially affected the evolution of various gene families. Its cultivated species G. max has high level of susceptibility to major pathogens including viruses, bacteria and fungi. Understanding nucleotide-binding domain leucine-rich repeat ( NLR ) genes evolution in soybean is of paramount importance due to their central role in plant immunity and their potential in improving disease resistance in soybean cultivars. In this study, we investigated the significance of this annual-perennial transition on the macroevolution of NLR genes in the genus Glycine . Our results reveal a remarkable distinction between annual species such as Glycine max and Glycine soja , which exhibit an expanded NLR ome compared to perennial species ( G. cyrtoloba, G. stenophita, G. dolichocarpa, G. falcata, G. syndetika, G. latifolia and G. tomentella ). Our evolutionary timescale analysis pinpoints recent accelerated gene duplication events for this expansion, which occurred between 0.1 and 0.5 million years ago, driven predominantly by lineage-specific and terminal duplications. In contrast, perennials initially experienced significant contraction during the diploidisation phase following the Glycine -specific whole-genome duplication event (~10 million years ago). Despite the reduction in the NLR ome, perennial lineages exhibit a unique and highly diversified repertoire of NLR genes with limited interspecies synteny. The investigation of gene gain and loss ratios revealed that this diversification resulted from the birth of novel genes following individual speciation events. Among perennials, G. latifolia , a well-known resistance resource, has the highest ratio of these novel genes in the tertiary gene pool. Our study suggests evolutionary mechanisms, including recombination and transposition, as potential drivers for the emergence of these novel genes. This study also provides evidence for the unbalanced expansion of the NLR ome in the D t subgenome compared with the A t subgenome in the young allopolyploid G. dolichocarpa . To the best of our knowledge, this is the first study to investigate the effect of annuality and perenniality life transition on the evolution of NLR genes in the genus Glycine to identify its genomics resources for improving the resistance of soybean crop with global importance on the economy and food security., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Sultan, Nawaz, Saleem, Nawaz, Danial, Iftikhar, Maqsood, Areej, Shakoor, Aljarba, Maqbool, Rizwan and Serfraz.)

The eighth workshop of the Worldwide Network for Blood and Marrow Transplantation (WBMT) was held in Islamabad, Pakistan, from September 22 to 23, 2022, aiming to foster hematopoietic stem cell transplant (HSCT) activity in the World Health Organization (WHO) Eastern Mediterranean Region (EMRO). Participating countries, including Pakistan, Oman, Iran, and Saudi Arabia, reported increased HSCT in the last few years, whereas others from the EMRO and beyond, including Qatar, United Arab Emirates, Nepal, and Bangladesh, started HSCT recently and have developed HSCT programs with excellent results. During educational sessions and open dialog, participating teams and international experts from the WBMT shared their experience and discussed minimum essential requirements for establishing and expanding HSCT in emerging countries, indications for HSCT training and dissemination of knowledge, stem cell donor selection and safety, quality assurance in transplant centers, and the value and importance of transplant outcome databases. International support, collaboration, and local engagement, including government participation and WHO assistance, are valuable in increasing HSCT access worldwide., (Copyright © 2024 Hematology/Oncology and Stem Cell Therapy.)

Hematopoietic stem cell transplant (HSCT) is potentially, the sole curative option for many malignant and non-malignant hematological disorders. Finding a human leukocyte antigen (HLA) compatible donor remains one of the limiting factors, hampering the utilization of HSCT. However, the introduction of post-transplant cyclophosphamide (PTCy) has improved the outcomes of haploidentical transplants making it a suitable option for patients lacking HLA-compatible donors. We collected data from 44 patients who underwent haplo-identical allogeneic stem cell transplants at the Armed Forces Bone Marrow Transplant Center/National Institute of Blood and Marrow Transplant (AFBMTC/NIBMT) from the year 2015 to 2022. The diseases were divided into three categories, i.e., bone marrow failure (BMF) syndromes, hematological malignancies (HM) and miscellaneous (Misc) groups. Median age at transplant was 18 (01-39) years. Transplant indications included aplastic anemia (AA) in 21 (47.7%) cases, 15 (34.1%) HM, and eight (18.2%) cases falling in the Misc groups. A maximum number of graft failures occurred in the BMF group; primary graft failure in 07 (33.3%) cases and secondary graft failure in four (19%) cases, (p-value < 0.05). Acute graft versus host disease (aGVHD) grade II-IV occurred in nine (20.5%) cases while chronic graft versus host disease (cGVHD) occurred in 10 (22.7%) cases. Cytomegalovirus (CMV) reactivation was seen in 31 (70.5%) cases. Maximum CMV reactivation was seen in HM group 13 (86.6%) cases, (p-value < 0.05) as compared to BMF (71.4%) and Misc groups (37.5%). Post-transplant cyclophosphamide (PTCy) based regimens, early neutrophil engraftment, and patients with GVHD had better survival outcomes (p-value < 0.05) overall survival (OS), and relapse-free survival (RFS). and GVHD-free relapse-free survival (GFRS) were significantly better in cases with early neutrophil engraftment. OS of the study cohort was 50% while disease-free survival (DFS) and GFRS were 45.5% and 36.4%, respectively., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Akram et al.)

Purpose: To highlight challenges and cancer care disparities in patients of diffuse large B-cell lymphoma management in resource-constrained settings., Materials and Methods: This multicenter retrospective study included 738 patients from 12 public and private sector hematology-oncology centers across Pakistan. Patients were divided into limited-resource and enhanced-resource settings as per national diffuse large B-cell lymphoma (DLBCL) guidelines., Results: The median age at diagnosis was 47 years (range, 14-89). Male:female ratio was 2.5:1. Majority of the patients (69.3%) were treated in limited-resource settings. Computed tomography was used as a staging modality in 442 (60%) patients. Limited-stage DLBCL was present in 13.5% of patients, while 86.3% had advanced-stage disease at diagnosis. First-line regimens included rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone in 56% and cyclophosphamide, doxorubicin, vincristine, prednisone in 34% of patients, while 10% of patients received palliative regimens upfront. Of evaluable data, complete remission was documented in 299 (74.4%) patients, 39 (9.8%) had partial response and 63 (13.5%) had progressive disease. Disease-free survival (DFS) and overall survival (OS) status were not available for 345 (46.8%) patients at the time of data collection. Overall study cohort had a median follow-up of 2.2 years with a median OS of 3.6 years (95% CI, 3.1 to 4.1), median DFS of 3.1 years (95% CI, 2.6 to 3.6), and a 5-year OS of 40% and DFS of 36%., Conclusion: Patients from low- and middle-income countries present at an earlier age and have more advanced disease. Patients were frequently lost to follow-up, and record keeping was inadequate more so in patients treated in limited-resource settings. There is a need to establish a national lymphoma registry, improve record keeping, and standardize treatments to ensure improvement in treatment outcomes.

Micheliolide (MCL) is a chief constituent of plants such as Magnolia grandiflora L. , Michelia compressa (Maxim.) Sarg . and Michelia champaca L. It is known to exhibit significant anticancer activity by various scientific investigations. This review aims to emphasize the anticancer and antiinflammatory activities of MCL. In this review, we summarized the published data in peer-reviewed manuscripts published in English. Our search was based on the following scientific search engines and databases: Scopus, Google Scholar, ScienceDirect, Springer, PubMed, and SciFinder, MCL possesses a broad spectrum of medicinal properties like other sesquiterpene lactones. The anticancer activity of this compound may be attributed to the modulation of several signaling cascades (PI3K/Akt and NF-κB pathways). It also induces apoptosis by arresting the cell cycle at the G1/G0 phase, S phase, and G2/M phase in many cancer cell lines. Very little data is available on its modulatory action on other signaling cascades like MAPK, STAT3, Wnt, TGFβ, Notch, EGFR, etc. This compound can be potentiated as a novel anticancer drug after thorough investigations in vitro , in vivo , and in silico -based studies., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Androgens represent the historical therapeutic backbone of bone marrow failure (BMF) syndromes. However, their role has rarely been analyzed in a prospective setting, and systematic and long-term data regarding their usage, effectiveness and toxicity in both acquired and inherited BMF are currently unavailable. Here, taking advantage of a unique disease-specific international dataset, we retrospectively analyzed the largest cohort so far of BMF patients who received androgens before or in the absence of an allogeneic hematopoietic cell transplantation (HCT), re-evaluating their current use in these disorders. We identified 274 patients across 82 European Society for Blood and Marrow Transplantation (EBMT) affiliated centers: 193 with acquired (median age 32 years) and 81 with inherited (median age 8 years) BMF. With a median duration of androgen treatment of 5.6 and 20 months, respectively, complete and partial remission rates at 3 months were 6% and 29% in acquired and 8% and 29% in inherited disorders. Five-year overall survival and failure-free survival (FFS) were respectively 63% and 23% in acquired and 78% and 14% in inherited BMF. Androgen initiation after second-line treatments for acquired BMF, and after >12 months post diagnosis for inherited BMF were identified as factors associated with improved FFS in multivariable analysis. Androgen use was associated with a manageable incidence of organ-specific toxicity, and low rates of solid and hematologic malignancies. Sub-analysis of transplant-related outcomes after exposure to these compounds showed probabilities of survival and complications similar to other transplanted BMF cohorts. This study delivers a unique opportunity to track androgen use in BMF syndromes and represents the basis for general recommendations on this category of therapeutics on behalf of the Severe Aplastic Anemia Working Party of the EBMT.

Photovoltaic (PV) materials, especially organic and perovskite solar cells are effective candidates for meeting the rising global energy demand. Herein, we have designed indolo[3,2- b ]indole-based six molecules (IDF1-IDF6) as hole-transporting materials (HTMs) for perovskite solar cells (PSCs) and donor materials for organic solar cells (OSCs). The results demonstrated that IDF1-IDF6 molecules have tight π-π stacking, more negative HOMO levels (-5.50 to -5.31 eV), low bandgaps (1.91 to 2.41 eV), high absorption coefficients, large Stokes shifts, high open-circuit photovoltages (1.31 to 1.50 V), and superior solubility with comparable stability compared with the reference (IDFR) and Spiro-OMeTAD molecules. The high light-harvesting efficiency and low exciton binding energy indicated that IDF1-IDF6 molecules have a higher photocurrent flow ability. The electronic excitation analyses of studied molecules showed that the IDF1-IDF6 molecules show stronger exciton dissociation, low charge coupling, and high intrinsic charge transfer with sharper charge flow than IDFR and Spiro-OMeTAD. Moreover, the high hole hopping rate, high total amount of charge transfer, and low reorganization energy with comparable charge transfer integral demonstrated that the designed molecules have effective hole transport ability for solar cells. Our remarkable results demonstrated that IDF1-IDF6 are advantageous molecules for the manufacturing of efficient PSCs and OSCs, and may have future commercial applications in the solar industry., Competing Interests: The authors declare no conflict of interest., (This journal is © The Royal Society of Chemistry.)

Solid waste leachate (SWL) requires dilution with water to offset the negative effects of high nutrient concentration and organic compounds for its microalgae-based treatment. Among attached cultivation systems, twin layer is a technology in which limited information is available on treatment of high strength wastewater using microalgae. Moreover, widespread application of twin layer technology is limited due to cost of substrate and source layer used. In the present study, potential of Scenedesmus sp. for the treatment of SWL was assessed on horizontal twin layer system (HTLS). Novel and cost-effective substrate layers were tested as attachment material. Wetland treated municipal wastewater (WMW) was used to prepare SWL dilutions viz, 5%, 10%, 15%, 20% and 25% SWL. Recycled printing paper showed maximum biomass productivity of 5.19 g m -2 d -1 . Among all the SWL dilutions, Scenedesmus sp. achieved maximum growth of 103.05 g m -2 in 5% SWL which was 16% higher than WMW alone. The maximum removal rate of NH 4 + -N, TKN, and PO 4 3- P was obtained in 20% SWL which was 1371, 1588 and 153 mg m -2 d -1 respectively. Varying concentrations of nutrients in different SWL dilutions significantly affected lipid biosynthesis, with enhanced productivity of 2.28 g m -2 d -1 achieved in 5% SWL compared to 0.97 g m -2 d -1 in 20% SWL. Hence, it can be concluded that 5% SWL dilution was good for biomass and lipid production, while the highest nutrient removal rates were obtained at 20% SWL mainly attributed to biotic and abiotic processes. Based on these results HTLS can be a promising technology for pilot scale to explore industrialized application of wastewater treatment and algal production., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Over the past few years, there have been tremendous developments in the design and synthesis of organic optoelectronic materials with appealing applications in device fabrication of organic light-emitting diodes, superconductors, organic lasers, organic field-effect transistors, clean energy-producing organic solar cells, etc. There is an increasing demand for the synthesis of green, highly efficient organic optoelectronic materials to cope with the issue of efficiency roll-off in organic semiconductor-based devices. This review systematically summarized the recent progress in the design and synthesis of small organic molecules having promising optoelectronic properties for their potential applications in optoelectronic devices during the last 10-year range (2010-early 2021)., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

In this study, four hole-transporting materials (JY-M1, JY-M2, JY-M3, and JY-M4) are designed by modifying benzothiadiazole-based core with diphenylamine-based carbazole via acceptors through thiophene linkers. The designed molecules exhibited deeper HOMO energy with smaller energy gaps than the reference JY molecule which enhance their hole mobility. The absorption spectra of the JY-M1, JY-M2, JY-M3, and JY-M4 molecules are located at 380 nm to 407 nm in the gaseous phase and 397 nm to 433 nm in the solvent phase, which is red-shifted and higher than the reference molecule, demonstrating that designed molecules possess improved light absorption properties and enhanced effective hole transfer. The dipole moments of the designed molecules (14.74 D to 26.12 D) indicate a greater ability for charge separation, solubility and will be beneficial to produce multilayer films. Moreover, the results of hole reorganization energy (0.38198 eV to 0.45304 eV) and charge transfer integral (0.14315 eV to 0.14665 eV) of designing molecules show improved hole mobility and lower recombination losses compared to the JY molecule. Overall, we suggested that the structural modifications in the designed molecules contributed to their enhanced efficiency in converting light energy into electrical energy and have the potential for utilization in solar devices, paving the way for future advancements in the field of photovoltaics., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Pakistan is the fifth most populous country with a population of 225 million and has health expenditure accounting for only 2.8 percent of gross domestic product (GDP). Accordingly, there are a limited number of haematology-oncology and transplant centers in the country. The Pakistan Blood and Marrow Transplant (PBMT) group was established in 2020, and this report is the first activity survey from January 2021 to December 2022 focusing on the trends of matched-related donor, haploidentical, and autologous transplants in a developing country. A total of 12 transplant centers contributed data on the modified PBMT survey form retrospectively and 806 haematopoietic stem cell transplants (HSCTs) were carried out during the study duration. Allogeneic HSCT constituted 595 (73.8%) of all the transplants; this is in stark contrast to Western data, where autologous HSCT accounts for the majority of transplants. ß -thalassemia major and aplastic anemia were the commonest indications for allogeneic HSCT, in contrast to Western data, where acute leukemia is the leading transplant indication. Autologous transplants were more frequently performed for Hodgkin's lymphoma as compared to non-Hodgkin's lymphoma and multiple myeloma. The use of peripheral and bone marrow stem cells was comparable. A myeloablative conditioning regimen was routinely used in patients with acute leukemia. This report provides an insight of HSCT trends in Pakistan which are different from those of Western centers contributing to transplant data from South Asia., Competing Interests: The authors declare that there are no conflicts of interest., (Copyright © 2023 Natasha Ali et al.)

Cytomegalovirus (CMV) infection is a major cause of morbidity and mortality after hematopoietic stem cell transplantation (HSCT). Limited data are available from developing countries regarding the frequency of CMV infection and treatment outcomes. We enrolled 230 consecutive patients undergoing allogeneic HSCT for various hematologic disorders at the Armed Forces Bone Marrow Transplant Center/National Institute of Blood And Marrow Transplant between February 2017 and December 202. CMV reactivation post-HSCT was monitored weekly starting at day +30 and continuing until day +100, and preemptive antiviral therapy was administered to prevent CMV disease in all HSCT recipients with ≥2000 CMV copies/mL. The median age of the study cohort was 9.5 years (range, .6 to 53 years), and the male:female ratio was 2.4:1. The most frequent indication for HSCT was beta thalassemia major (36.1%), followed by aplastic anemia (23.9%). Malignant disorders constituted 20% of all the patients. Pretransplantation CMV seropositivity was 99.1% for the recipients and 99.5% for the donors. CMV infection was seen in 66.1% of the patients, and the median time to CMV DNAemia was 36 days (range, 12 to 95 days). Preemptive antiviral therapy was administered to 140 patients with a CMV viral load ≥2000 copies/mL (61%). In multivariate analysis, patient age >12 years, steroid administration, and use of mycophenolate mofetil with or without post-transplantation cyclophosphamide was associated with the greatest probability of CMV reactivation. Overall survival was 97.4% in patients without CMV reactivation, compared to 80.3% in those with CMV reactivation (P = .001). Event-free survival was 78.7% in the total study cohort, including 89.7% for patients without CMV reactivation and 73% for patients with CMV reactivation (P = .003). Our study is the first from this region to explore the frequency of CMV seropositivity and CMV infection, risk factors for CMV reactivation, and outcomes of antiviral therapy in HSCT recipients., (Copyright © 2023 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Background: Aplastic anaemia is a rare bone marrow failure syndrome and is defined by pancytopenia associated with a hypo-cellular bone marrow with no increase in reticulin and the absence of any abnormal infiltrate. The objective of the study was to determine the frequency of Aldehyde Dehydrogenase type 2 (ALDH2) deficiency in patients with Aplastic Anaemia and investigate its correlation with patient and disease characteristics. It was a descriptive cross-sectional study conducted at Armed Forces Bone Marrow Transplant Centre Rawalpindi from 01-08-2022-01-02-2023, over 6 months., Methods: A total of 56 patients who were diagnosed with aplastic anaemia during this period, fulfilling inclusion criteria were enrolled. Patients were genotyped as GG (homozygous) and GA (heterozygous). GG had normal ALDH2, while GA were patients with ALDH2 deficiency. Data was collected on the patient's demographics, type and severity of anaemia, type of hematopoietic stem cell transplant (HSCT) and frequency of ALDH2 deficiency. Results were analyzed for ALDH2 deficiency and its correlation with patient and disease characteristics was investigated., Results: A total of 56 patients were included in the study. The median age of the patients was 28 years (20-39). According to the type of aplastic anaemia, 2 (3.6%) had Fanconi anaemia and 54 (96.4%) had acquired aplastic anaemia. In our study, 18 (32.1%) patients had undergone HSCT while the remaining 38 (67.9%) could not undergo HSCT. The frequency of the presence of ALDH2 deficiency was 2 (3.6%). There was no statistically significant correlation between the frequency of ALDH2 deficiency with variables like gender, age distribution, type of aplastic anaemia, the severity of aplastic anaemia and hematopoietic stem cell transplant., Conclusions: We concluded from our study the frequency of ALDH2 was rare in patients with aplastic anaemia. There was no statistically significant correlation between the frequency of ALDH2 deficiency with variables like gender, age distribution, type of aplastic anaemia, the severity of aplastic anaemia and hematopoietic stem cell transplant.

Onion thrips (Thrips tabaci Lindeman, Thysanoptera: Thripidae) causes severe damage to many horticultural and agronomic crops worldwide. It also acts as a vector of several plant viruses. T. tabaci is a key pest of Allium cepa in the United States. However, there is limited information available on the genetic variation within and between T. tabaci populations in the United States and its key evolutionary parameters. In the current study, 83 T. tabaci specimens were collected from A. cepa from 15 different locations comprising four states of the United States. A total of 92 mtCOI gene sequences of T. tabaci from A. cepa were analyzed to understand the genetic diversity and structure of T. tabaci collected from onion host. Seven distinct haplotypes of T. tabaci infesting A. cepa were identified from the current collection, while nine T. tabaci sequences retrieved from GenBank comprised 5 haplotypes. Overall, 15 haplotypes of T. tabaci infesting A. cepa were identified in the world that includes the ten haplotypes in the United States. In the phylogenetic analysis, all the populations collected during the study clustered with thelytokous lineage, while T. tabaci sequences retrieved from GenBank corresponded to leek-associated arrhenotokous lineage. The highest genetic variation was found in Elba and Malheur populations with 3 haplotypes identified in each. The results suggest that haplotypes 1 and 7 are more frequently prevailing haplotypes in the north-western United States, with haplotype 1 being the predominant all over the country. The eastern United States appears to have a more diverse group of haplotypes. The populations from Hungary constituted distinct haplotypes and a haplotype from Kingston linked it with the predominant haplotype., (© The Author(s) 2023. Published by Oxford University Press on behalf of Entomological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Inflammatory bowel disease (IBD), characterized by infiltration of polymorphonuclear neutrophils (PMNs), increases the risk of colon cancer. PMN activation corresponds to the accumulation of intracellular Lipid Droplets (LDs). As increased LDs are negatively regulated by transcription factor Forkhead Box O3 (FOXO3), we aim to determine the significance of this regulatory network in PMN-mediated IBD and tumorigenesis. Affected tissue of IBD and colon cancer patients, colonic and infiltrated immune cells, have increased LDs' coat protein, PLIN2. Mouse peritoneal PMNs with stimulated LDs and FOXO3 deficiency have elevated transmigratory activity. Transcriptomic analysis of these FOXO3-deficient PMNs showed differentially expressed genes (DEGs; FDR < 0.05) involved in metabolism, inflammation, and tumorigenesis. Upstream regulators of these DEGs, similar to colonic inflammation and dysplasia in mice, were linked to IBD and human colon cancer. Additionally, a transcriptional signature representing FOXO3-deficient PMNs (PMN-FOXO3 389 ) separated transcriptomes of affected tissue in IBD ( p = 0.00018) and colon cancer ( p = 0.0037) from control. Increased PMN-FOXO3 389 presence predicted colon cancer invasion (lymphovascular p = 0.015; vascular p = 0.046; perineural p = 0.03) and poor survival. Validated DEGs from PMN-FOXO3 389 ( P2RX1, MGLL, MCAM, CDKN1A, RALBP1, CCPG1, PLA2G7 ) are involved in metabolism, inflammation, and tumorigenesis ( p < 0.05). These findings highlight the significance of LDs and FOXO3-mediated PMN functions that promote colonic pathobiology.

Bone marrow failure syndromes are a heterogeneous group of diseases. With the major advancements in diagnostic tools and sequencing techniques, these diseases may be better classified and therapies may be further tailored. Androgens, a historic group of drugs, were found to stimulate hematopoiesis by enhancing the responsiveness of progenitors. These agents have been used for decades to treat different forms of bone marrow failure. With the availability of more effective pathways to treat BMF, androgens are less used currently. Nevertheless, this group of drugs may serve BMF patients where standard therapy is contraindicated or not available. In this article, we review the published literature addressing the use of androgens in BMF patients and we make recommendations on how to best use this class of drugs within the current therapeutic landscape., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Nassani, Fakih, Passweg, Cesaro, Alzahrani, Alahmari, Bonfim, Iftikhar, Albeihany, Halkes, Ahmed, Dufour and Aljurf.)

Ynamides are N -alkyne compounds bearing an electron withdrawing group at the nitrogen atom. They offer unique pathways for the construction of versatile building blocks owing to their exceptional balance between reactivity and stability. Recently several studies have been reported that explore and illustrate the synthetic potential of ynamides and ynamide-derived advanced intermediates in cycloadditions with different reaction partners to yield heterocyclic cycloadducts of synthetic and pharmaceutical value. Cycloaddition reactions of ynamides are the facile and preferable routes for the construction of structural motifs having striking importance in synthetic, medicinal chemistry, and advanced materials. In this systematic review, we highlighted the recently reported novel transformations and synthetic applications that involved the cycloaddition reaction of ynamides. The scope along with the limitations of the transformations are discussed in detail., Competing Interests: The authors have no conflict of interest to declare., (This journal is © The Royal Society of Chemistry.)

The obesity epidemic is associated with increased colorectal cancer (CRC) risk and progression, the mechanisms of which remain unclear. In obese individuals, hypertrophic epiploic adipose tissue (EPAT), attached to the colon, has unique characteristics compared to other fats. We hypothesized that this understudied fat could serve as a tumor-promoting tissue and developed a novel microphysiological system (MPS) for human EPAT-dependent colorectal cancer (CRC-MPS). In CRC-MPS, obese EPAT, unlike lean EPAT, considerably attracted colon cancer HT29-GFP cells and enhanced their growth. Conditioned media (CM) from the obese CRC-MPS significantly increased the growth and migration of HT29 and HCT116 cells ( p < 0.001). In HT29 cells, CM stimulated differential gene expression (hOEC 867 ) linked to cancer, tumor morphology, and metabolism similar to those in the colon of high-fat-diet obese mice. The hOEC 867 signature represented pathways found in human colon cancer. In unsupervised clustering, hOEC 867 separated transcriptomes of colon cancer samples from normal with high significance (PCA, p = 9.6 × 10 -11 ). These genes, validated in CM-treated HT29 cells ( p < 0.05), regulate the cell cycle, cancer stem cells, methylation, and metastasis, and are similarly altered in human colon cancer (TCGA). These findings highlight a tumor-promoting role of EPAT in CRC facilitated with obesity and establishes a platform to explore critical mechanisms and develop effective treatments.

Well-known Betti bases are the products obtained by the one-pot multicomponent reaction of 1-naphthol/2-naphthol, aliphatic/aromatic aldehydes, and secondary amines, and this reaction is known as the Betti reaction. During recent years, due to the unveiling of the pharmacological and synthetic potential of Betti bases, a tremendous increase in the studies reporting novel synthetic methods for the efficient synthesis of Betti bases was observed. This review presents the recent key developments in the green synthesis of the Betti bases and accounts for the significant number of the literature reported during 2019-2022. Both catalyst free as well as the catalyst promoted synthesis (nanocatalyst, biocatalyst, transition metal catalyst, etc.) along with the synthetic applications (catalyst, ligands/chiral auxiliaries, and valuable synthons), optoelectronic applications (fluorescence sensors for phosgene gas, Hg 2+ , and Cr 3+ detection, quasi-reversible redox potential) and biological properties (anticancer agents, antioxidant, anti-inflammatory agents, antitubercular agents, pesticidal agents, anti-Alzheimer agents, Topoisomerase I inhibitors, YAP-TEAD interaction inhibitors, and DNA binding and cleavage activity) are discussed. There is a surge of interest for the development of the green and efficient Betti reaction for the construction of C-C and C-N bond in a single-step reaction accessing Betti bases as products. Along with key methodological developments for the green synthesis of Betti bases, their applications in synthetic organic chemistry, optoelectronic sensors, advanced materials synthesis, agrochemicals and pharmaceutically active scaffolds, during the period of 2019-2022, have been considered., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)