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Abstract Background Hereditary motor and sensory neuropathy (HMSN) refers to a group of inherited progressive peripheral neuropathies characterized by reduced nerve conduction velocity with chronic segmental demyelination and/or axonal degeneration. HMSN is highly clinically and genetically heterogeneous with multiple inheritance patterns and phenotypic overlap with other inherited neuropathies and neurodegenerative diseases. Due to this high complexity and genetic heterogeneity, this study aimed to elucidate the genetic causes of HMSN in Pakistani families using Whole Exome Sequencing (WES) for variant identification and Sanger sequencing for validation and segregation analysis, facilitating accurate clinical diagnosis. Methods Families from Khyber Pakhtunkhwa with at least two members showing HMSN symptoms, who had not previously undergone genetic analysis, were included. Referrals for genetic investigations were based on clinical features suggestive of HMSN by local neurologists. WES was performed on affected individuals from each family, with Sanger sequencing used to validate and analyze the segregation of identified variants among family members. Clinical data including age of onset were assessed for variability among affected individuals, and the success rate of genetic diagnosis was compared with existing literature using proportional differences and Cohen’s h. Results WES identified homozygous pathogenic variants in GDAP1 (c.310 + 4 A > G, p.?), SETX (c.5948_5949del, p.(Asn1984Profs*30), IGHMBP2 (c.1591 C > A, p.(Pro531Thr) and NARS1 (c.1633 C > T, p.(Arg545Cys) as causative for HMSN in five out of nine families, consistent with an autosomal recessive inheritance pattern. Additionally, in families with HMSN, a SETX variant was found to cause cerebellar ataxia, while a NARS1 variant was linked to intellectual disability. Based on American College of Medical Genetics and Genomics criteria, the GDAP1 variant is classified as a variant of uncertain significance, while variants in SETX and IGHMBP2 are classified as pathogenic, and the NARS1 variant is classified as likely pathogenic. The age of onset ranged from 1 to 15 years (Mean = 5.13, SD = 3.61), and a genetic diagnosis was achieved in 55.56% of families with HMSN, with small effect sizes compared to previous studies. Conclusions This study expands the molecular genetic spectrum of HMSN and HMSN plus type neuropathies in Pakistan and facilitates accurate diagnosis, genetic counseling, and clinical management for affected families.

Abstract Background Hereditary Spastic Paraplegias (HSPs) and Hereditary Cerebellar Ataxias (HCAs) are progressive neurodegenerative disorders encompassing a spectrum of neurogenetic conditions with significant overlaps of clinical features. Spastic ataxias are a group of conditions that have features of both cerebellar ataxia and spasticity, and these conditions are frequently clinically challenging to distinguish. Accurate genetic diagnosis is crucial but challenging, particularly in resource-limited settings. This study aims to investigate the genetic basis of HSPs and HCAs in Pakistani families. Methods Families from Khyber Pakhtunkhwa with at least two members showing HSP or HCA phenotypes, and who had not previously been analyzed genetically, were included. Families were referred for genetic analysis by local neurologists based on the proband’s clinical features and signs of a potential genetic neurodegenerative disorder. Whole Exome Sequencing (WES) and Sanger sequencing were then used to identify and validate genetic variants, and to analyze variant segregation within families to determine inheritance patterns. The mean age of onset and standard deviation were calculated to assess variability among affected individuals, and the success rate was compared with literature reports using differences in proportions and Cohen’s h. Results Pathogenic variants associated with these conditions were identified in five of eight families, segregating according to autosomal recessive inheritance. These variants included previously reported SACS c.2182 C > T, p.(Arg728*), FA2H c.159_176del, p.(Arg53_Ile58del) and SPG11 c.2146 C > T, p.(Gln716*) variants, and two previously unreported variants in SACS c.2229del, p.(Phe743Leufs*8) and ZFYVE26 c.1926_1941del, p.(Tyr643Metfs*2). Additionally, FA2H and SPG11 variants were found to have recurrent occurrences, suggesting a potential founder effect within the Pakistani population. Onset age among affected individuals ranged from 1 to 14 years (M = 6.23, SD = 3.96). The diagnostic success rate was 62.5%, with moderate effect sizes compared to previous studies. Conclusions The findings of this study expand the genotypic and phenotypic spectrum of HSPs and HCAs in Pakistan and emphasize the importance of utilizing exome/genome sequencing for accurate diagnosis or support accurate differential diagnosis. This approach can improve genetic counseling and clinical management, addressing the challenges of diagnosing neurodegenerative disorders in resource-limited settings.

Abstract B-cell malignancies, such as chronic lymphocytic leukemia (CLL) and multiple myeloma (MM), remain incurable, with MM particularly prone to relapse. Our study introduces a novel mouse model with active RANK signaling and the TCL1 oncogene, displaying both CLL and MM phenotypes. In younger mice, TCL1 and RANK expression expands CLL-like B1-lymphocytes, while MM originates from B2-cells, becoming predominant in later stages and leading to severe disease progression and mortality. The induced MM mimics human disease, exhibiting features like clonal plasma cell expansion, paraproteinemia, anemia, and kidney and bone failure, as well as critical immunosurveillance strategies that promote a tumor-supportive microenvironment. This research elucidates the differential impacts of RANK activation in B1- and B2-cells and underscores the distinct roles of single versus combined oncogenes in B-cell malignancies. We also demonstrate that human MM cells express RANK and that inhibiting RANK signaling can reduce MM progression in a xenotransplantation model. Our study provides a rationale for further investigating the effects of RANK signaling in B-cell transformation and the shaping of a tumor-promoting microenvironment.

Abstract Background Intellectual disability (ID) is a neurodevelopmental condition affecting around 2% of children and young adults worldwide, characterized by deficits in intellectual functioning and adaptive behavior. Genetic factors contribute to the development of ID phenotypes, including mutations and structural changes in chromosomes. Pathogenic variants in the HCFC1 gene cause X-linked mental retardation syndrome, also known as Siderius type X-linked mental retardation. The MN1 gene is necessary for palate development, and mutations in this gene result in a genetic condition called CEBALID syndrome. Methods Exome sequencing was used to identify the disease-causing variants in two affected families, A and B, from various regions of Pakistan. Affected individuals in these two families presented ID, developmental delay, and behavioral abnormalities. The validation and co-segregation analysis of the filtered variant was carried out using Sanger sequencing. Results In an X-linked family A, a novel hemizygous missense variant (c.5705G > A; p.Ser1902Asn) in the HCFC1 gene (NM_005334.3) was identified, while in family B exome sequencing revealed a heterozygous nonsense variant (c.3680 G > A; p. Trp1227Ter) in exon-1 of the MN1 gene (NM_032581.4). Sanger sequencing confirmed the segregation of these variants with ID in each family. Conclusions The investigation of two Pakistani families revealed pathogenic genetic variants in the HCFC1 and MN1 genes, which cause ID and expand the mutational spectrum of these genes.

Abstract Recent studies suggest that noninvasive imaging methods (EEG, MEG) in the human brain scalp can decode the content of visual features information (orientation, color, motion, etc.) in Visual-Working Memory (VWM). Previous work demonstrated that with the sustained low-frequency Event-Related Potential (ERP under 6 Hz) of scalp EEG distributions, it is possible to accurately decode the content of orientation information in VWM during the delay interval. In addition, previous studies showed that the raw data captured by a combination of the occi-parietal electrodes could be used to decode the orientation. However, it is unclear whether the orientation information is available in other frequency bands (higher than 6 Hz) or whether this information is feasible with fewer electrodes. Furthermore, the exploration of orientation information in the phase values of the signal has not been well-addressed. In this study, we propose that orientation information is also accessible through the phase consistency of the occipital region in the alpha band frequency. Our results reveal a significant difference between orientations within 200 ms after stimulus offset in early visual sensory processing, with no apparent effect in power and Event-Related Oscillation (ERO) during this period. Additionally, in later periods (420–500 ms after stimulus offset), a noticeable difference is observed in the phase consistency of low gamma-band activity in the occipital area. Importantly, our findings suggest that phase consistency between trials of the orientation feature in the occipital alpha and low gamma-band can serve as a measure to obtain orientation information in VWM. Furthermore, the study demonstrates that phase consistency in the alpha and low gamma band can reflect the distribution of orientation-selective neuron numbers in the four main orientations in the occipital area.

Abstract Background Epilepsy, a challenging neurological condition, is often present with comorbidities that significantly impact diagnosis and management. In the Pakistani population, where financial limitations and geographical challenges hinder access to advanced diagnostic methods, understanding the genetic underpinnings of epilepsy and its associated conditions becomes crucial. Methods This study investigated four distinct Pakistani families, each presenting with epilepsy and a spectrum of comorbidities, using a combination of whole exome sequencing (WES) and Sanger sequencing. The epileptic patients were prescribed multiple antiseizure medications (ASMs), yet their seizures persist, indicating the challenging nature of ASM-resistant epilepsy. Results Identified genetic variants contributed to a diverse range of clinical phenotypes. In the family 1, which presented with epilepsy, developmental delay (DD), sleep disturbance, and aggressive behavior, a homozygous splice site variant, c.1339–6 C > T, in the COL18A1 gene was detected. The family 2 exhibited epilepsy, intellectual disability (ID), DD, and anxiety phenotypes, a homozygous missense variant, c.344T > A (p. Val115Glu), in the UFSP2 gene was identified. In family 3, which displayed epilepsy, ataxia, ID, DD, and speech impediment, a novel homozygous frameshift variant, c.1926_1941del (p. Tyr643MetfsX2), in the ZFYVE26 gene was found. Lastly, family 4 was presented with epilepsy, ID, DD, deafness, drooling, speech impediment, hypotonia, and a weak cry. A homozygous missense variant, c.1208 C > A (p. Ala403Glu), in the ATP13A2 gene was identified. Conclusion This study highlights the genetic heterogeneity in ASM-resistant epilepsy and comorbidities among Pakistani families, emphasizing the importance of genotype-phenotype correlation and the necessity for expanded genetic testing in complex clinical cases.

Gene expression profiling is a powerful tool that has been extensively used to investigate the underlying biology and etiology of diseases, including cancer. Microarray gene expression analysis enables simultaneous measurement of thousands of mRNA levels. Sophisticated computational approaches have evolved in parallel with the rapid progress in bioassay technologies, enabling more effective analysis of the large and complex datasets that these technologies produce.In this study, we utilized systems biology approaches to examine gene expression profiles across different grades of breast cancer progression. We conducted a meta-analysis of publicly available microarray data to elucidate the molecular mechanisms underlying breast cancer grade classification.Our results suggest that while grade index is commonly used for evaluating cancer progression status in the clinic, the complexity of molecular mechanisms, histological characteristics, and other factors related to patient outcomes raises doubts about the utility of breast cancer grades as a foundation for formulating treatment protocols.Our study underscores the importance of advancing personalized strategies for breast cancer classification and management. More research is crucial to refine diagnostic tools and treatment modalities, aiming for greater precision and tailored care in patient outcomes.

Abstract The perception of color is a fundamental cognitive feature of our psychological experience, with an essential role in many aspects of human behavior. Several studies used magnetoencephalography, functional magnetic resonance imaging, and electroencephalography (EEG) approaches to investigate color perception. Their methods includes the event-related potential and spectral power activity of different color spaces, such as Derrington-Krauskopf-Lennie and red-green-blue (RGB), in addition to exploring the psychological and emotional effects of colors. However, we found insufficient studies in RGB space that considered combining all aspects of EEG signals. Thus, in the present study, focusing on RGB stimuli and using a data-driven approach, we investigated significant differences in the perception of colors. Our findings show that beta oscillation of green compared to red and blue colors occurs in early sensory periods with a latency shifting in the occipital region. Furthermore, in the occipital region, the theta power of the blue color decreases noticeably compared to the other colors. Concurrently, in the prefrontal area, we observed an increase in phase consistency in response to the green color, while the blue color showed a decrease. Therefore, our results can be used to interpret the brain activity mechanism of color perception in RGB color space and to choose suitable colors for more efficient performance in cognitive activities.

Identifying spatial clusters of rabies in animals aids policymakers in allocating resources for rabies prevention and control. This study aimed to investigate spatial patterns and hotspots of rabies in different animal species at the county level in New Jersey. Data on animal rabies cases from January 1989 to December 2023 were obtained from the New Jersey Department of Health and aggregated by county. Global Moran’s index (I) statistics were computed for each species to detect global spatial clustering (GeoDa version 1.22). Local Moran’s indicators of spatial association (LISA) were computed to identify local clusters of rabies. The results from the LISA analysis were mapped using ArcGIS Pro to pinpoint cluster locations. A total of 9637 rabies cases were analyzed among raccoons (n = 6308), skunks (n = 1225), bats (n = 1072), cats (n = 597), foxes (n = 225), and groundhogs (n = 210). A global Moran’s test indicated significant global spatial clustering in raccoons (I = 0.32, p = 0.012), foxes (I = 0.29, p = 0.011), and groundhogs (I = 0.37, p = 0.005). The LISA results revealed significant spatial clustering of rabies in raccoons and foxes in southeastern New Jersey and in groundhogs in northern New Jersey. These findings could guide the development of targeted oral rabies vaccination programs in high-risk New Jersey counties, reducing rabies exposure among domestic animals and humans.

This study examined the impact of the 2017 Veterinary Feed Directive (VFD) rule changes on the prevalence of tetracycline-resistant and erythromycin-resistant bacteria (Salmonella spp., Campylobacter spp., and Escherichia coli) in cecal samples of food animals (cattle, swine, chicken, and turkey) at US slaughterhouses. Multivariable logistic regression was used to analyze 2013–2019 cecal samples of food-producing animals surveillance data from the National Antimicrobial Resistance Monitoring System (NARMS) in the U.S. The variables included year (used to evaluate VFD rule changes), host, and quarter of year. The analysis of surveillance data showed that the VFD rule changes have varying effects on tetracycline-resistant and erythromycin-resistant bacteria in food animals. For example, the odds of detecting tetracycline-resistant Salmonella spp. decreased in cattle but increased in chickens following the implementation of the VFD rule changes. Similarly, the odds of detecting tetracycline-resistant Escherichia coli decreased in chickens but increased in swine after the VFD rule changes. The odds of detecting erythromycin-resistant Campylobacter spp. increased in cattle but decreased in chickens after the VFD rule changes. In conclusion, the implementation of VFD rule changes has been beneficial in reducing the odds of detecting tetracycline-resistant Escherichia coli and erythromycin-resistant Campylobacter spp. in chickens, as well as tetracycline-resistant Salmonella spp. in cattle at US slaughterhouses.

Abstract Background Tuberculosis (TB) has been an important public health concern in Bangladesh. The most common cause of human TB is Mycobacterium tuberculosis, while bovine TB is caused by Mycobacterium bovis. Objective The objective of this study was to determine the frequency of TB in individuals with occupational exposure to cattle and to detect Mycobacterium bovis among cattle in slaughterhouses in Bangladesh. Methods Between August 2014 and September 2015, an observational study was conducted in two government chest disease hospitals, one cattle market, and two slaughterhouses. [Correction added on 27 June 2023, after first online publication: In the preceding sentence, the year “2014” has been added after the word “August”.] Sputum samples were collected from individuals who met the criteria for suspected TB and had been exposed to cattle. Tissue samples were collected from cattle that had low body condition score(s). Both humans and cattle samples were screened for acid‐fast bacilli (AFB) by Ziehl–Neelsen (Z‐N) staining and cultured for Mycobacterium tuberculosis complex (MTC). Region of difference (RD) 9‐based polymerase chain reaction (PCR) was also performed to identify Mycobacterium spp. We also conducted Spoligotyping to identify the specific strain of Mycobacterium spp. Results Sputum was collected from a total of 412 humans. The median age of human participants was 35 (IQR: 25–50) years. Twenty‐five (6%) human sputum specimens were positive for AFB, and 44 (11%) were positive for MTC by subsequent culture. All (N = 44) culture‐positive isolates were confirmed as Mycobacterium tuberculosis by RD9 PCR. Besides, 10% of cattle workers were infected with Mycobacterium tuberculosis in the cattle market. Of all TB (caused by Mycobacterium tuberculosis) infected individuals, 6.8% of individuals were resistant to one or two anti‐TB drugs. The majority of the sampled cattle (67%) were indigenous breeds. No Mycobacterium bovis was detected in cattle. Conclusions We did not detect any TB cases caused by Mycobacterium bovis in humans during the study. However, we detected TB cases caused by Mycobacterium tuberculosis in all humans, including cattle market workers.

Abstract Background Retinitis Pigmentosa (RP) is a clinically and genetically progressive retinal dystrophy associated with severe visual impairments and sometimes blindness, the most common syndromic form of which is Usher syndrome (USH). This study aimed to further increase understanding of the spectrum of RP in the Khyber Pakhtunkhwa region of Pakistan. Methodology Four consanguineous families of Pashtun ethnic group were investigated which were referred by the local collaborating ophthalmologists. In total 42 individuals in four families were recruited and investigated using whole exome and dideoxy sequencing. Among them, 20 were affected individuals including 6 in both family 1 and 2, 5 in family 3 and 3 in family 4. Result Pathogenic gene variants were identified in all four families, including two in cone dystrophy and RP genes in the same family (PDE6C; c.480delG, p.Asn161ThrfsTer33 and TULP1; c.238 C > T, p.Gln80Ter) with double-homozygous individuals presenting with more severe disease. Other pathogenic variants were identified in MERTK (c.2194C > T, p.Arg732Ter), RHO (c.448G > A, p.Glu150Lys) associated with non-syndromic RP, and MYO7A (c.487G > A, p.Gly163Arg) associated with USH. In addition, the reported variants were of clinical significance as the PDE6C variant was detected novel, whereas TULP1, MERTK, and MYO7A variants were detected rare and first time found segregating with retinal dystrophies in Pakistani consanguineous families. Conclusions This study increases knowledge of the genetic basis of retinal dystrophies in families from Pakistan providing information important for genetic testing and diagnostic provision particularly from the Khyber Pakhtunkhwa region.

Background & aim: Primary dysmenorrhea is one of the most common complaints in women. This study compared the effect of ginger-lavender, ginger and mefenamic acid capsules on the severity of primary dysmenorrhea among female university students.Methods: This randomized, triple-blind clinical trial was performed in 2020 on 90 female students with primary dysmenorrhea, who lived in dormitories of Shahid Beheshti University of Medical Sciences, Tehran, Iran and randomly assigned to three groups. During the first three days of menstruation, the students received ginger-lavender (250 mg ginger and 50 mg lavender extract), ginger (250 mg), and mefenamic acid (250 mg) in two consecutive cycles, which were prescribed four times daily for three days from the onset of menstruation. A menstrual status questionnaire, verbal multidimensional scoring system, and visual analog scale were used to measure pain duration and intensity before and two cycles after intervention. Data were analyzed using two-way (intragroup) and one-way (intergroup) repeated measures ANOVA.Results: Ginger- lavender, ginger and mefenamic acid significantly reduced the severity and duration of primary dysmenorrhea (P 0.05). This decrease was greater in the ginger-lavender group than in the other two groups. Also, the mean score of pain in the ginger-lavender group was 1.04 and 1.53 units lower than the ginger and mefenamic acid groups, respectively. The mean pain score in the ginger group was 0.49 units lower than that the mefenamic acid group.Conclusion: Ginger-lavender significantly reduced the duration and severity of menstrual pain and was more effective than only ginger and mefenamic acid.

Objective Polycystic ovary syndrome (PCOS) is an endocrine disorder that disrupts the menstrual cycle and causes infertility. Considering the increasing use of medicinal plants, the present study aimed to evaluate the effects of Teucrium polium L. on letrozole-induced PCOS in female rats. Methods Six groups of rats (n=7 each) were evaluated. The control group received 1% carboxy methyl cellulose as vehicle, while the five other groups received letrozole 1 mg/kg orally for 21 days. After PCOS induction, the rats were orally administered T. polium extract (50, 100, and 200 mg/kg) or metformin (200 mg/kg) for 28 days. Subsequently, body and ovarian weights and serum levels of follicle stimulating hormone, luteinizing hormone (LH), estradiol, progesterone, and testosterone were measured. Finally, the ovarian tissues were isolated for histological examination. Results There were no significant changes in weekly body weight in any group. After 21 days of letrozole administration, PCOS induction was confirmed by estrous cycle irregularities and increased LH and testosterone levels. After treatment with the hydroalcoholic extract of T. polium, testosterone and LH levels were significantly reduced in all groups (P

Abstract Purpose Women of reproductive age who carry fragile X premutation (PM) alleles have 56 to 200 CGG repeats in the 5′-untranslated region of FMR1 gene are at increased risk for producing children with intellectual disabilities (ID) or autism spectrum disorders (ASD) due to expansion of PM alleles to full mutation alleles (> 200 repeats) during maternal transmission. Methods In present study fragile X PM carrier screening was performed in total 808 women who were consulting primary health care centers for preconception care in Khyber Pakhtunkhwa region of Pakistan between April, 2018 and December, 2020. Polymerase chain reaction (PCR) was performed for detection of PM carrier women and the CGG repeats number was confirmed by Southern blotting and capillary electrophoresis. Results The prevalence rate for PM carriers among preconception women was found to be 0.7% that was contributed by 0.5% women in risk group (RG1) with family history of ID and 0.2% in risk group 2 (RG2) with family history of ASD. PM carrier women had at least one affected child or sibling. In addition, the preconception women with FMR1 PM alleles were found to be at increased risk for primary ovary insufficiency (RG1: P = 0.0265, RG2: P = 0.0389), postpartum depression (RG1: P = 0.0240, RG2: P = 0.0501) and neuropsychiatric disorders (RG1: P = 0.0389, RG2: P = 0.0432). Conclusions Current study provides first evidence of fragile X PM carrier screening in Pakistani preconception women in primary care consultation. Findings of current study may help to improve preconception care and to reduce burden of fragile X associated disorders in our population.

Background and purpose: Peripheral neuropathy is one of the most common adverse effects of cancer chemotherapy. Vincristine is prescribed to treat a variety of carcinomas, including lymphoma and leukemia, and may cause progressive peripheral neuropathy due to the damage of microtubules and mitochondria of neurons and affects inflammatory processes. This study was designed to evaluate the effects of Lavandula angustifolia hydroalcoholic extract (LHE) of aerial part on vincristine-induced peripheral neuropathy in a rat model. Experimental approach: Neuropathy was induced in rats by daily intraperitoneal administration of vincristine (0.1 mg/kg for 2 weeks). Following the induction of neuropathy, animals were treated with the LHE (100, 200, and 400 mg/kg, p.o.) or pregabalin (20 mg/kg, IP) for 2 weeks, and their responses to vincristine-induced hyperalgesia and locomotor impairment were measured. Findings/Results: LHE, at the dose of 400 mg/kg, showed analgesic effects in response to thermal hyperalgesia, tactile allodynia, and gait impairment. Also, pregabalin (20 mg/kg, IP) improved the symptoms of vincristine-induced peripheral neuropathy. Conclusions and implications: According to the results, we can conclude that LHE alleviates neuropathic symptoms of vincristine and the effect is probably related to the presence of phenols and flavonoids in the extract.

Introduction: Dysmenorrhea‌ is a‌ major problem‌ in women's‌ general and ‌individual health. Complications of nonsteroidal anti-inflammatory drugs (NSAIDs) in this disease have led to an increase in the tendency to complementary, alternative and herbal remedies. ‌This study was performed with aim to compare the effect of‌ "Ginger-Lavender"‌ capsule with" Mefenamic Acid"‌ on the severity of primary dysmenorrhea. Methods: This triple-blind clinical trial study was conducted in in 2020 on 60 students with a history of primary dysmenorrhea living in the selected dormitories of Shahid Beheshti University of Medical Sciences. The research tools were the questionnaire of menstrual status, demographic and anthropometric characteristics form and pain line. In the intervention group, Ginger-Lavender capsules and in the control group, Mefenamic Acid capsules were prescribed four times daily for 3 days from the onset of menstruation bleeding. Pain intensity was measured during 2 months. Data were analyzed by SPSS software (version 24) and independent t-test,‌ Bonferroni, Fisher, and Analysis of Variance. P

BackgroundAntimicrobial-resistant bacteria are a growing public health threat. In 2017 the U.S. Food and Drug Administration implemented Veterinary Feed Directive (VFD) rules changes to limit medically important antimicrobial use in food-producing animals, combating antimicrobial-resistant bacteria. The effect of the VFD rule changes on the occurrence of bacteria resistant to medically-important antimicrobials in retail meats is yet to be investigated in the U.S. This study investigates whether the VFD rule changes affected the occurrence of tetracycline-resistant and erythromycin-resistant bacteria (Salmonella, Escherichia, and Campylobacter) in retail meats in the U.S.MethodsMultivariable mixed effect logistic regression models were used to analyze 2002-2019 retail meats surveillance data from the National Antimicrobial Resistance Monitoring System (NARMS) in the U.S. Variables included VFD rule changes, meat type, quarter of year, and raising claims. A potential association between these variables and the occurrence of tetracycline-resistant and erythromycin-resistant bacteria (Salmonella, Escherichia, and Campylobacter) in retail meats was estimated.ResultsAnalysis included data regarding tetracycline-resistant Salmonella (n = 8,501), Escherichia (n = 20, 283), Campylobacter (n = 9,682), and erythromycin-resistant Campylobacter (n = 10,446) in retail meats. The odds of detecting tetracycline-resistant Escherichia (OR = 0.60), Campylobacter (OR = 0.89), and erythromycin-resistant Campylobacter (OR = 0.43) in chicken breast significantly decreased after the VFD rule changes, compared to the pre-VFD rule change period. The odds of detecting tetracycline-resistant Salmonella (0.66), Escherichia (OR = 0.56), and Campylobacter (OR = 0.33) in ground turkey also significantly decreased. However, the odds of detecting tetracycline-resistant Salmonella (OR = 1.49) in chicken breast and erythromycin-resistant Campylobacter (OR = 4.63) in ground turkey significantly increased. There was no significant change in the odds of detecting tetracycline-resistant Salmonella and Escherichia in ground beef or pork chops.ConclusionsThe implementation of VFD rule changes had a beneficial effect by reducing the occurrence of tetracycline-resistant and erythromycin-resistant bacteria in chicken and ground turkey. Ongoing surveillance of antimicrobial resistance and antimicrobial use could complement the implementation of stewardship such as VFD rule in food-producing animals in the U.S.

AIM: To investigate the genetic basis of autosomal recessive retinitis pigmentosa (arRP) in two consanguineous/ endogamous Pakistani families. METHODS: Whole exome sequencing (WES) was performed on genomic DNA samples of patients with arRP to identify disease causing mutations. Sanger sequencing was performed to confirm familial segregation of identified mutations, and potential pathogenicity was determined by predictions of the mutations' functions. RESULTS: A novel homozygous frameshift mutation [NM_000440.2:c.1054delG, p. (Gln352Argfs*4); Chr5:g.149286886del (GRCh37)] in the PDE6A gene in an endogamous family and a novel homozygous splice site mutation [NM_033100.3:c.1168-1G>A, Chr10:g.85968484G>A (GRCh37)] in the CDHR1 gene in a consanguineous family were identified. The PDE6A variant p. (Gln352Argfs*4) was predicted to be deleterious or pathogenic, whilst the CDHR1 variant c.1168-1G>A was predicted to result in potential alteration of splicing. CONCLUSION: This study expands the spectrum of genetic variants for arRP in Pakistani families.

Introduction: Postpartum pain is one of the common postpartum problems that has adverse consequences for both mother and infant. The side effects of chemical drugs have led to the tendency to use herbal medicines to reduce postpartum pain. This study was performed with aim to investigate the effect of Saliva hydrangea capsule on postpartum pain. Methods: This double-blind randomized clinical trial study was performed in 2018 on 100 mothers that 2 hours had passed from their normal vaginal delivery and had severity of moderate to severe postpartum pain based on visual pain scale (VAS). The women were randomly assigned in two groups: Saliva hydrangea+mefenamic acid and placebo+mefenamic acid. The capsules were used every 6 hours. The intensity and duration of pain were recorded before and one hour after the intervention by VAS. Data were analyzed by SPSS software (version 21) and independent- t and paired t-test, Mann-Whitney U test and repeated measures. P

Breast cancer (BC) is a complex disease caused by molecular events that disrupt cellular survival and death. Discovering novel biomarkers is still required to better understand and treat BC. The reticulon-4 (RTN4) gene, encoding Nogo proteins, plays a critical role in apoptosis and cancer development, with genetic variations affecting its function. We investigated the rs34917480 in RTN4 and its association with BC risk in an Iranian population sample. We also predicted the rs34917480 effect on RTN4 mRNA structure and explored the RTN4’s protein–protein interaction network (PPIN) and related pathways. In this case–control study, 437 women (212 BC and 225 healthy) were recruited. The rs34917480 was genotyped using AS-PCR, mRNA secondary structure was predicted with RNAfold, and PPIN was constructed using the STRING database. Our findings revealed that this variant was associated with a decreased risk of BC in heterozygous (p = 0.012), dominant (p = 0.015), over-dominant (p = 0.017), and allelic (p = 0.035) models. Our prediction model showed that this variant could modify RTN4’s mRNA thermodynamics and potentially its translation. RTN4’s PPIN also revealed a strong association with apoptosis regulation and key signaling pathways highly implicated in BC. Consequently, our findings, for the first time, demonstrate that rs34917480 could be a protective factor against BC in our cohort, probably via preceding mechanisms.

Abstract Background Retinitis pigmentosa (RP) is the most common inherited retinal dystrophy, affecting approximately 1 in 4000 individuals worldwide. The most common form of syndromic RP is Usher syndrome (USH) accounting for approximately 20–30 % of RP cases. Mutations in the USH2A gene cause a significant proportion of recessive non-syndromic RP and USH type II (USH2). This study aimed to determine the causative role of the USH2A gene in autosomal recessive inherited ocular diseases and to establish genotype-phenotype correlation associated with USH2A variants. Methods We performed direct Sanger sequencing and co-segregation analysis of the USH2A gene to identify disease causing variants in a non-syndromic RP family, two USH2 families and two Keratoconus (KC) families. Results Disease causing variants in the USH2A gene were identified in two families displayed KC and USH2 phenotypes. A novel variant c.4029T > G, p.Asn1343Lys in the USH2A gene was detected in a Pakistani family with KC phenotype. In addition, a missense variant (c.7334 C > T, p. Ser2445Phe) in the USH2A gene was found segregating in another Pakistani family with USH2 phenotype. Homozygosity of identified missense USH2A variants was found associated with autosomal recessive inherited KC and USH2 phenotypes in investigated families. These variants were not detected in ethnically matched healthy controls. Moreover, the USH2A variants were predicted to be deleterious or potentially disease causing by PolyPhen-2, PROVEAN and SIFT. Conclusions This study provided first evidence for association of a novel USH2A variant with KC phenotype in a Pakistani family as well as established the phenotype-genotype correlation of a USH2A variant (c.7334 C > T, p. Ser2445Phe) with USH2 phenotype in another Pakistani family. The phenotype-genotype correlations established in present study may improve clinical diagnosis of affected individuals for better management and counseling.

Introduction: It is important to pay attention to the sexual function of women of childbearing age due to long-term conflict with it and its impact on personal health, marital relations and childbearing. The phytoestrogenic effect of the Vitex agnus-castus plant on sexual function of postmenopausal women as well as in limited animal studies has been shown to improve, enhance sexual behavior and hormones, but it has not been studied in women of childbearing age. Therefore, this study was performed with aim to determine the effect of Vitex agnus-castus plant consumption on sexual dysfunction in women of childbearing age. Methods: This double-blind clinical trial study was performed on 102 women referred to Alzahra Women's Clinic of Rasht for doing Pap smears in 2019. Eligible candidates completed the Female Sexual Function Index (FSFI) questionnaire; if they were placed in the group of sexual dysfunction and then randomly assigned to two groups of Vitex agnus-castus tablet or placebo. FSFI questionnaire was again completed after 4 weeks. Data were analyzed by SPSS software (version 21) and Chi-square, Fisher, Mann-Whitney, Independent-t and paired t-test. P

Abstract Background and objectives NF-kB, SIRT1 and systemic inflammation factors including hs-CRP, IL-6 and TNF-α accelerate atherosclerosis pathogenesis. Our purpose was to evaluate the effect of daily supplementation of three-gram cinnamon on plasma levels of NF-kB, SIRT, hs-CRP, IL-6 and TNF-α among type 2 diabetes patients. Subjects and methods A randomized, double blind, and controlled clinical trial was performed with 44 adult patients who were 25 to 70 years old with type 2 diabetes, randomized to two intervention (n = 22) and control (n = 22) groups differing by daily three grams cinnamon supplementation and placebo for 8 weeks, respectively. The plasma levels of NF-kB, SIRT, hs-CRP, IL-6 and TNF-α were measured by ELISA assay at the beginning and end of the study. Results After 8-week intervention, 39 subjects (n = 20 in the cinnamon and n = 19 in the placebo groups) ended up the trial. It was not observed significant difference in levels of hs-CRP (P = 0.29), TNF-α (P = 0.27), IL-6 (P = 0.52), and Sirtuin-1 (P = 0.51) in between group comparison. While, the result showed significant difference in levels of NF-kB (P = 0.02) between groups. As well as, in among group comparison, there was not observed significant differences except in hs-CRP (P = 0.008) in placebo group. Conclusions This study elucidated that cinnamon supplementation has no beneficial effects in reduction of NF-kB, SIRT1, hs-CRP, IL-6 and TNF-α levels in type 2 diabetes patients which have a considerable role in development of atherogenesis.

Foods that contain antibiotic residues have potential adverse health effects on consumers and provide selective pressure for the threat of antimicrobial resistance (AMR). This study’s objective was to measure tetracycline, sulfonamide, and erythromycin residues in beef, eggs, and honey sold as “antibiotic-free” at farmers’ markets in East Tennessee (East TN) in the United States (U.S.). Between July and September 2020, 36 “antibiotic-free” food products (9 beef, 18 egg, and 9 honey products) were purchased from East TN farmers’ markets and tested for tetracycline, sulfonamide, and erythromycin residues using competitive enzyme-linked immunosorbent assays (cELISA). All beef, egg, and honey products had tetracycline residue; the median concentrations were 51.75, 30.25, and 77.86 µg/kg, respectively. Sulfonamide residue was present in every sample of beef. Of 18 eggs, 11 eggs had detectable sulfonamide residue; the median concentrations were 3.50 and 1.22 µg/kg in beef and eggs, respectively. Each sample of beef and honey contained erythromycin residue; the median concentrations were 3.67 and 0.68 µg/kg, respectively. Overall, the median concentrations of tetracycline, sulfonamide, and erythromycin residues were below the maximum residue levels (MRLs) set in the U.S. for beef and eggs. Thus, the beef and eggs sold as “antibiotic-free” in East TN farmers’ markets can be considered safe for consumption. Safety determination for honey could not be made because MRLs have not been set for honey in the U.S. Because these residues should not be expected in “antibiotic-free” food products, it is important to further investigate the potential sources of these residues in these products.

The presence of antibiotic residues in the tissue of food animals is a growing concern due to the adverse health effects that they can cause in humans, such as antibiotic resistance bacteria. An inspector-generated sampling (IGS) dataset from the United States National Residue Surveillance Program, collected between 2014 and 2019, was analyzed to investigate the association of changes in the veterinary feed directive (VFD) regulations on the detection of violative penicillin, tetracycline, sulfonamide, desfuroylceftiofur, tilmicosin, and florfenicol, residues in the tissue of food animals. Multivariable logistic regression models were used for analysis. While the animal production class was significantly associated with residue violations for tetracycline, having a sample collection date after the implementation of change in VFD regulations was not. However, the odds of detecting violative sulfonamide and penicillin residues in the tissue of food animals following the implementation of the change in VFD regulations were 36% and 24% lower than those collected before the implementation of the change in VFD regulations period, respectively, irrespective of animal production class. Violative desfuroylceftiofur, tilmicosin, and florfenicol residues in the tissue of food animals were not significantly associated with the implementation of changes in the VFD regulations. Further investigation of the factors that influence the presence of violative antibiotic residues in the tissue of food animals following the change in VFD regulations would lend clarity to this critical issue.

Background: Nitric oxide and reactive nitrogen species play an important role in various pathological conditions like cancer, inflammation and neurodegeneration. As plants and natural compounds have a great potency of discovering lead compounds which might affect NO production during inflammation and various pathologies, we examined the effects of three medicinal plants native to Iran, on NO production during oxidative stress in PC12 cells. Methods: In this study, cell death and NO levels were measured by MTT and by Griess assay, respectively. Oxidative stress was induced by hydrogen peroxide and extracts of Astragalus jolderensis, Convolvulus commutatus and Salvia multicaulis were used as pretreatment in oxidative stressed PC12 cells. Results: A. jolderensis extract significantly suppressed NO production in 150 and 200 μg/ml concentrations and C. commutatus extract in all concentration inhibited NO production in stressed PC12 cells. In addition, the extract of S. multicaulis inhibited NO production during stress at all concentrations above 50 μg/ml. Besides, the extract of S. multicaulis showed protective effect at lower doses in stressed cells. Conclusion: According to the results, S. multicaulis inhibited NO production and protected cells from oxidative stress. Hence, S. multicaulis is a good candidate for further in vitro and in vivo investigations. A. jolderensis and C. commutatus also suppressed NO production during stress. Therefore, they could be noticed in experiments that centralize on the inhibition of NO production and drug discovery studies in the field of neurodegenerative and chronic inflammatory diseases.

BACKGROUND: Pregnancy causes a set of complex physiological and psychological changes that affect marital relationships. Mindfulness is a form of meditation that can promote person's performance and perception of sexual relationships. The present study aimed to determine the effect of mindfulness on sexual desire and sexual satisfaction in primigravida pregnant women. MATERIALS AND METHODS: The present study is a quasi-experimental that has investigated on 72 primigravida pregnant women. The samples were selected randomly and assigned to experimental and control groups. The experimental group received six 90-min sessions of mindfulness intervention, and the control group received the educational pamphlet. The female sexual function index (FSFI) was filled by the subjects of the two groups in three stages of before the intervention, a week, and a month after the intervention. Data analysis was done by SPSS20 (Statistics 20 software; SPSS Inc., Chicago, IL, USA) at the significance level of 0.05. RESULTS: According to the statistical tests, there was no significant difference between the two groups in terms of demographic characteristics and pregnancy information. The findings suggest no significant difference between the mean pretest and posttest score of sexual desire in the two groups (P > 0.05). However, the two groups were significantly different in terms of the mean score of sexual satisfaction before and after the intervention (P

Background and purpose: Due to the properties of Stevia, it seems that this plant can be effective in reducing oxidative damage consequent to ischemia-reperfusion, and increase the survival of skin flap. This research aimed at investigating the effects of oral extract of stevia on apoptosis and skin flap necrosis in rats. Materials and methods: In this experimental study, Sprague Dawley rats were orally gavaged 25 mg/kg/daily of stevia leaf extract for one week, before or after the removal of flap. One week after surgery, the amount of flap necrosis, the content of malondialdehyde (MDA) in flap tissue, and superoxide dismutase (SOD) activity were measured. Results: Pre-treatment or post-treatment with stevia leaf extract reduced the necrotic area in the flap compared to the control group. It also reduced the MDA content and increased SOD activity. Pre-treatment with stevia leaf extract was found to have a better protective effect than post-treatment in all variables investigated. Conclusion: Current findings confirmed the survival of the flap with oral administration of stevia leaf extract. The beneficial effects of oral extract of stevia leaf can be clinically examined in reducing ischemic flap necrosis before and after surgery.

Abstract Background Autosomal recessive anophthalmia and microphthalmia are rare developmental eye defects occurring during early fetal development. Syndromic and non-syndromic forms of anophthalmia and microphthalmia demonstrate extensive genetic and allelic heterogeneity. To date, disease mutations have been identified in 29 causative genes associated with anophthalmia and microphthalmia, with autosomal dominant, autosomal recessive and X-linked inheritance patterns described. Biallelic ALDH1A3 gene variants are the leading genetic causes of autosomal recessive anophthalmia and microphthalmia in countries with frequent parental consanguinity. Methods This study describes genetic investigations in two consanguineous Pakistani families with a total of seven affected individuals with bilateral non-syndromic clinical anophthalmia. Results Using whole exome and Sanger sequencing, we identified two novel homozygous ALDH1A3 sequence variants as likely responsible for the condition in each family; missense mutation [NM_000693.3:c.1240G > C, p.Gly414Arg; Chr15:101447332G > C (GRCh37)] in exon 11 (family 1), and, a frameshift mutation [NM_000693.3:c.172dup, p.Glu58Glyfs*5; Chr15:101425544dup (GRCh37)] in exon 2 predicted to result in protein truncation (family 2). Conclusions This study expands the molecular spectrum of pathogenic ALDH1A3 variants associated with anophthalmia and microphthalmia, and provides further insight of the key role of the ALDH1A3 in human eye development.

MicroRNAs by their structural complementarity capabilities have canonical roles in gene regulation. In this paper; we investigate expression of EGFR, MAP2K4 and E2F3 genes targeted by miR-141, a member of miR-200 family. EGFR, MAP2K4 and E2F3 were predicted as the potential targets of mir-141 by using online miRNA bioinformatics tools. MCF-7 cells were transfected with mir-141-precursor and inhibitor vectors. Expression of miR-141 and target genes was determined by using qRT-PCR. To see the most relevant pathways regulated by miR-141, we constructed two separate networks by NetworkAnalyst and enriched list of underlying genes by Enrichment analysis tools. The expression changes of all three predicted targets were higher in transfected cells with anti-mir-141 vector, compared with the control untransfected cells. By contrast, in transfected cells with pre-mir 141, we did not see significant expression changes in EGFR, E2F3 and MAP2K4. List of genes in total networks as well as explored functional modules were enriched separately. Enrichment analysis shows that immune system pathway has the strongest relationship with the proteins potentially targeted by miR-141. The present study demonstrated potential role of miR-141 in regulation of EGFR, MAP2K4 and E2F3 expression and suggested innate immunity pathways as the key pathway through which this regulatory network contributes to breast cancer development.

BACKGROUND: Sexual dysfunction in women is a common disorder. Yet, there is no consensus on its treatment. Few studies have shown that Vitex agnus-castus improves sexual dysfunction in postmenopausal women; the present study was conducted to evaluate the effect of V. agnus-castus on the female sexual function in the reproductive age. MATERIALS AND METHODS: This was a double-blinded randomized control clinical trial on the women of reproductive age referred to the gynecology clinic of Al-Zahra Medical Center in Rasht, Iran, from February 2018 to December 2019. The intervention group received Agnugol tablet containing 3.2–4.8 mg dried extract V. agnus-castus (51 participants) and the control group received a placebo tablet (51 participants). All participants received one tablet daily for 16 weeks. The participants were asked to complete the Female Sexual Function Index questionnaire at the beginning of the study and after 4, 8, 12, and 16 weeks. Data were analyzed in SPSS statistics (version 21) using Chi-square test, t-test, Mann–Whitney U-test, analysis of variance, and mixed model to examine the differences between the groups. RESULTS: The results showed that the difference between the two groups was not significant in each domain, but there was a significant difference in the overall sexual function mean score so that the intervention group had a higher score than the placebo group after 16 weeks (P < 0.05). CONCLUSION: In the present study, it was observed that the consumption of V. agnus-castus during 16 weeks was more effective than the placebo in improving sexual dysfunction. Further studies with larger sample sizes are needed to be able to decide on the prescription of this drug in the clinics.

AIM: To map Usher phenotype in a consanguineous Pakistani family and identify disease-associated mutation in a causative gene to establish phenotype-genotype correlation. METHODS: A consanguineous Pakistani family in which Usher phenotype was segregating as an autosomal recessive trait was ascertained. On the basis of results of clinical investigations of affected members of this family disease was diagnosed as Usher syndrome (USH). To identify the locus responsible for the Usher phenotype in this family, genomic DNA from blood sample of each individual was genotyped using microsatellite Short Tandem Repeat (STR) markers for the known Usher syndrome loci. Then direct sequencing was performed to find out disease associated mutations in the candidate gene. RESULTS: By genetic linkage analysis, the USH phenotype of this family was mapped to PCDH15 locus on chromosome 10q21.1. Three different point mutations in exon 11 of PCDH15 were identified and one of them, c.1304A>C was found to be segregating with the disease phenotype in Pakistani family with Usher phenotype. This, c.1304A>C transversion mutation predicts an amino-acid substitution of aspartic acid with an alanine at residue number 435 (p.D435A) of its protein product. Moreover, in silico analysis revealed conservation of aspartic acid at position 435 and predicated this change as pathogenic. CONCLUSION: The identification of c.1304A>C pathogenic mutation in PCDH15 gene and its association with Usher syndrome in a consanguineous Pakistani family is the first example of a missense mutation of PCDH15 causing USH1 phenotype. In previous reports, it was hypothesized that severe mutations such as truncated protein of PCDH15 led to the Usher I phenotype and that missense variants are mainly responsible for non-syndromic hearing impairment.

Dasatinib is a common anticancer drug used in the treatment of leukemia. Several side effects have been reported, the most common being myelosuppression, diarrhea, edema, and nausea. Three papers have been published reporting hepatic side effects of dasatinib treatment. A rare side effect of dasatinib treatment is reactivation of latent cytomegalovirus (CMV) infection. Never before has dasatinib therapy shown to be the cause of CMV hepatitis in an immunocompetent patient. We present a case of an immunocompetent patient who was treated with the standard dose of dasatinib therapy and subsequently developed CMV hepatitis. Well-known side effects of dasatinib therapy are understood and documented; unknown adverse drug reactions can occur and should be monitored for. This is a significant finding given the high rate of CMV seropositivity in the general population.

Peste des petits Ruminants (PPR) is an acute, febrile, highly contagious and economically important viral disease of small ruminants. However PPR is more prevalent in sheep and goat. Competitive ELISA, Virus neutrilization test, and RT-PCR are the available techniques for diagnosis of PPR which give rapid detection where as Agar gel immunodiffusion and Counter immunoelectrophoresis were previously used for PPR detection. In this study two serological techniques were compared for PPR diagnosis. The main aim of this study was to evaluate the comparative sensitivity of both techniques for PPR detection. For this purpose one hundred and sixty PPR suspected serum samples collected from goats and sheep flocks (unvaccinated) from three Districts of NWFP including Mardan, Hangu and Kohat were analyzed in National Veterinary Laboratories, Islamabad. Out of these 160 samples, fifty (50) were found positive for PPR antibodies with cELISA (Prevalence = 31.25%). The cELISA positive serum samples however gave negative results when tested with AGID although the control well was always positive. Thus it was concluded that cELISA technique is more sensitive and specific than AGID for PPR antibody detection. [Vet. World 2009; 2(3.000): 89-92]

Under solvent-free conditions, different alcohols and phenols were efficiently acetylated at room temperature within short time periods by using acetic anhydride in the presence of catalytic quantities of sodium acetate trihydrate, which is a very inexpensive and mild reagent. Thiols were also shown to behave equally well under the same conditions. Chemoselective protection of less hindered alcohols in the presence of bulkier homologues and phenols in the presence of alcohols was achieved using competitive experiments.

Purpose: Patients with Germ cell tumours (GCT) are at risk of long-term toxicities due to multimodality therapy. It is debatable whether there is an impact on the quality of life(QoL) of GCT survivors., Methods: A case-control study was conducted at a tertiary care centre in India, using the EORTC QLQ C30 questionnaire, to compare the QoL between GCT survivors(disease free > 2 years) and healthy matched controls. A multivariate regression model was used to identify factors affecting QoL., Results: A total of 55 cases and 100 controls were recruited. Cases had a median age of 32 years (interquartile range, IQR 28-40 years), ECOG PS of 0-1(75%), advanced stage III (58%), chemotherapy (94%) and 66% were > 5 years from diagnosis. The median age of controls: 35 years (IQR 28-43 years). A statistically significant difference was seen for emotional (85.8 ± 14.2 vs 91.7 ± 10.4, p 0.005), social(83.0 ± 22.0 vs 95.2 ± 9.6, p < 0.001) and global scales (80.4 ± 21.1 vs 91.3 ± 9.7, p < 0.001). Cases had more nausea and vomiting(3.3 ± 7.4 vs 1.0 ± 3.9, p 0.015), pain(13.9 ± 13.9 vs 4.8 ± 9.8, p < 0.001), dyspnea(7.9 + 14.3 vs 2.7 ± 9.1, p 0.007), and appetite loss(6.7 ± 14.9 vs 1.9 ± 7.9, p 0.016) and greater financial toxicity(31.5 ± 32.3 vs 9.0 ± 16.3, p < 0.001). Adjusting for age, performance status, BMI, stage, chemotherapy, RPLND, recurrent disease, and time since diagnosis, no predictive variables were significant., Conclusion: There is a detrimental impact of history of GCT in long term survivors of GCT., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Abstract: Kikuchi-Fujimoto disease (KFD) is a rare benign condition associated with fever and lymphadenopathy and was first described by Kikuchi and Fujimoto independently in 1972 as histiocytic necrotizing lymphadenitis. The diagnosis is made by histopathology with immunohistochemistry. Limbic encephalitis is an extremely rare presentation of this uncommon disease, which has been described mainly in children. Available evidence is sparse in the form of case reports and case series in the form of 10 cases published till date. We report a case of an adult female with KFD with autoimmune limbic encephalitis, who had complete clinical and radiologic recovery with treatment, and a literature review of all the cases published till date., (Copyright © 2024 Copyright: © 2024 Annals of Indian Academy of Neurology.)

We describe a rare occurrence of bilateral acute severe sensorineural hearing loss in a middle-aged man that heralded the diagnosis of metastatic gastric cancer., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Primary thoracic synovial sarcoma (PTSS) is a rare malignancy presenting with varying clinical manifestations. There is a paucity of data with few studies dedicated to this unique subset of neoplasms. We present our findings from one of the largest real-world studies among patients with PTSS., Methods: This is a single-centre, real-world study in patients with PTSS included between 2017 and 2023. Survival estimates were obtained by the Kaplan-Meier method and Cox regression analysis., Results: 24 patients with a median age of 34.5 years (range 16-54) presented with chest pain ( n = 11, 45.8%) and dyspnea ( n = 10, 41.6%). Predominant primary sites of disease were the lung ( n = 12, 50%) and mediastinum ( n = 6, 25%). The stage at presentation was unresectable locally advanced ( n = 10, 41.6%), localised ( n = 8, 33.3%) and metastatic ( n = 6, 25%) with pulmonary metastases ( n = 10, 62.5%) and pleural effusion ( n = 4, 25%). 16 (66.6%) patients underwent surgical resection including 7 (43.8%) who received neoadjuvant chemotherapy (NACT). NACT was given in ten patients producing stable disease in 5 (50%) and partial response in 3 (30%) patients, respectively, with surgery performed in 7 (70%). 11 (62.5%) operated patients had a microscopically complete resection and 10 (41.6%) received postoperative radiotherapy. Anthracyclines were given in 23 (95.8%) patients in the first line, while pazopanib was the most common therapy in the second and third lines, respectively. At a median follow-up of 32 months (range 16.7-47.2), the median overall survival (OS) was 41 months (95% CI: 23.7-58.2) and 8 months (95% CI: 1-25.6) overall and in metastatic disease, respectively. Presentation with metastases ( p = 0.01) and treatment with surgical resection ( p = 0.005) were significantly associated with OS on univariate analysis., Interpretation: The locally advanced nature of the disease at presentation signifies the need for early diagnosis and technically superior definitive therapies. The survival outcomes for metastatic disease remain poor and the need for novel therapies for advanced disease remains unmet so far., Clinical Trial Registration: Not applicable., Competing Interests: The authors have no conflicts of interest to declare., (© the authors; licensee ecancermedicalscience.)

Paraneoplastic neurologic syndromes are cancer-associated, immune-mediated neurologic manifestations that may involve any part of the nervous system. They usually present with characteristic neurologic features and should be considered in high-risk phenotypes such as limbic encephalitis, encephalomyelitis, rapidly progressive cerebellar syndrome, opsoclonus-myoclonus, sensory neuronopathy, enteric neuropathy, and Lambert-Eaton myasthenic syndrome. The diagnosis is made by antibody positivity in the serum or cerebrospinal fluid, in the presence of an appropriate clinical phenotype. Findings on antibody testing by immunoblot should always be verified by immunofluorescence. We report a rare case of sensory neuronopathy with triple paraneoplastic antibody positivity (anti-Hu, anti-collapsing response-mediator protein 5, and anti-amphiphysin) on immunoblot but only anti-Hu positivity on immunofluorescence. The presence of lower facial dyskinesias should raise the possibility of an immune-mediated neurologic syndrome in the appropriate clinical context., (Copyright © 2024 Copyright: © 2024 Annals of Indian Academy of Neurology.)

We aimed to evaluate the utility of simple, cost-effective, and non-invasive strategies alternative to BIPSS and peripheral CRH stimulation in differential diagnosis of ACTH-dependent CS. First, we performed ROC analysis to evaluate the performance of various tests for differential diagnosis of ACTH-dependent CS in our cohort (CD, n=76 and EAS, n=23) and derived their optimal cut-offs. Subsequently, combining various demographic (gender), clinical (hypokalemia), biochemical (plasma ACTH, HDDST, peripheral CRH stimulation) and imaging (MRI pituitary) parameters, we derived non-invasive models with 100% PPV for CD. Patients with pituitary macroadenoma (n=14) were excluded from the analysis involving non-invasive models. Relative percent ACTH (AUC: 0.933) and cortisol (AUC: 0.975) increase on peripheral CRH stimulation demonstrated excellent accuracy in discriminating CD from EAS. Best cut-offs for CD were plasma ACTH<97.3 pg/ml, HDDST≥57% cortisol suppression, CRH stimulation≥77% ACTH increase and≥11% cortisol increase. We derived six models that provided 100% PPV for CD and precluded the need for BIPPS in 35/85 (41.2%) patients with ACTH-dependent CS and no macroadenoma (in whom BIPSS would have otherwise been recommended). The first three models included basic parameters and avoided both peripheral CRH stimulation and BIPSS in 19 (22.4%) patients, while the next three models included peripheral CRH stimulation and avoided BIPSS in another 16 (18.8%) patients. Using simple and non-invasive alternative strategies, BIPSS can be avoided in 41% and peripheral CRH stimulation in 22% of patients with ACTH-dependent CS and no macroadenoma; such patients can be directly referred for a pituitary surgery., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Introduction: Prostate cancer is one of the most prevalent malignancies affecting men globally, with a significant impact on health-related quality of life (HRQOL). With the recent therapeutic advancements and improvements in survival, there is a need to understand the determinants of HRQOL in metastatic prostate cancer patients to optimize treatment strategies for quality of life as the number of survivors increases. The aim of this study was to identify clinical variables that affect HRQOL and its domains in patients with metastatic prostate cancer., Methods: We conducted a cross-sectional questionnaire-based study in patients diagnosed with metastatic prostate cancer at a tertiary cancer center in India. Baseline clinical features, treatment details, and completed Functional Assessment of Cancer Therapy-Prostate (FACT-P), composed of FACT-general (FACT-G) and prostate cancer-specific concerns subscale (PCS) and FACT-P Trial Outcome Index (FACT-P TOI) questionnaires, were collected. The mean total, as well as individual domain scores, were calculated. Additionally, these were stratified by the current treatment being received by patients. Linear regression was used to identify independent factors affecting HRQOL in these patients., Results: Of the 106 enrolled patients, 84 completed the FACT-P questionnaire and were included in the analysis. The median age was 66 years, and at the time of assessment, 3 patients (3.6%) were receiving androgen deprivation therapy only, 53 patients (63.1%) were on ADT + androgen receptor-targeted agents (ARTAs), and 18 patients (21.4%) patients received ADT + chemotherapy. The mean (±standard deviation) of the FACT-P TOI score was 70.33 (±15.16); the PCS subscale was the most affected, followed by functional well-being. Patients on chemotherapy scored significantly higher on PCS, but the composite scores were not significantly different. Univariable regression identified obesity (body mass index > 25 kg/m 2 ) and duration of first-line treatment as significant predictors of better HRQOL; however, obesity was the only independent predictor in multivariable analysis (β = 8.2; 95% confidence interval, 1.2 to 15.0; p = 0.022). Obesity also independently predicted a better FACT-P and its physical well-being domain score and PCS., Conclusion: Prostate cancer patients experience impaired QoL, especially in the prostate cancer-specific and functional well-being domains. Lower BMI is an independent predictor of poor QoL, and this requires efforts to assess the impact of strategies to manage the nutritional status of patients with metastatic disease on QoL outcomes.

Objective: Hepatocellular carcinoma (HCC) with portal vein thrombosis (PVT) have limited therapeutic options, Re-188 lipiodol transarterial therapy being one of them. We aimed to assess the safety and efficacy of Re-188 lipiodol exclusively in HCC with PVT as well as to compare two chelating agents for the synthesis of Re-188 lipiodol: novel bis-(diethyldithiocarbamato) nitrido (N-DEDC) with existing acetylated 4-hexadecyl 1-2,9,9-tetramethyl-4,7-diaza-1,10-decanethiol [(A)HDD]., Methods: Patients with radiological diagnosis of HCC with PVT having Eastern Cooperative Oncology Group (ECOG) performance status ≤2 and Child Pugh score (PS) A or B were recruited. Patients received an empirical dose of transarterial Re-188 lipiodol, labelled with (A)HDD or N-DEDC. Radiological response on MRI (modified response evaluation criteria in solid tumors), biochemical response with serum alpha fetoprotein and clinical response with ECOG PS was assessed at three months and survival was estimated at the end of the study., Results: Fifteen therapies were performed in 14 patients with a median age of 62 years (range: 41-70 years). Eight therapies were with Re-188 (A)HDD lipiodol and seven with Re-188 N-DEDC lipiodol. Overall mean injected dose was 2.6 ± 0.37 GBq. Radiological objective response rate was 31% and disease control rate was 85%. Mean overall survival was 14.21 months and mean progression free survival was 10.23 months. Percentage survival assessed at 3, 6 and 9 months was 93%, 64% and 57%, respectively. Safety parameters, response and survival outcome were comparable for (A)HDD and N-DEDC groups., Conclusion: Transarterial Re-188 lipiodol in HCC with PVT is safe and effective in disease control as well as improving survival outcome. Additionally, cost-effective and high-yielding novel agent N-DEDC appears to be a comparable alternative to (A)HDD for the same., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Neuroblastoma presenting with multiple muscles and subcutaneous tissue metastases is rarely reported in the literature. We would like to highlight such infrequent occurrences for increasing the clinical acumen of the medical fraternity with an aim to deliver proper therapy to patients., Competing Interests: There are no conflicts of interest., (Copyright: © 2024 Indian Journal of Nuclear Medicine.)

Background: Approximately 20%-25% of patients with metastatic castration-resistant prostate cancer (mCRPC) harbor a deleterious germline or somatic mutation in the homologous recombination repair (HRR) pathway genes, which is involved in the repair of double-stranded DNA damage. Half of these mutations are germline, while the remaining are exclusively somatic. While polyadenosine 5'diphosphoribose [poly (ADP-ribose)] polymerase inhibitors, such as olaparib and rucaparib, are effective in this subgroup, their widespread use is limited due to the associated high cost, especially in resource-constrained settings. Notably, platinum agents like carboplatin have exquisite sensitivity to cells with defective DNA repair machinery. Carboplatin, a conventional, inexpensive chemotherapeutic agent, offers a potential alternative treatment in such patients. Several retrospective small case series support this hypothesis. However, there are no prospective clinical trials of carboplatin in patients with mCRPC with HRR mutations., Objective: The primary objective is to assess the objective response rate of 3 weekly carboplatin treatments in patients with mCRPC harboring deleterious mutations in the HRR pathway genes and previously treated with a taxane or a novel antiandrogen agent. The secondary objectives include progression-free survival, health-related quality of life, and safety profile of carboplatin., Methods: Patients diagnosed with mCRPC harboring HRR pathway mutations previously treated with docetaxel or novel antiandrogen agents (abiraterone, enzalutamide, apalutamide, or darolutamide) or both will be eligible. Genes involved directly or indirectly in the HRR pathway will be tested. In this single-arm phase II study, we will screen approximately 200 patients to enroll 49 patients, and carboplatin (dosing at the area under curve=5) will be administered every 3 weeks until progression or intolerable side effects. The primary end point will be assessed as the proportion of patients with a reduction of serum prostate-specific antigen by more than 50% from enrollment. Secondary outcomes include progression-free survival-soft-tissue disease progression (by response evaluation criteria in solid tumors, version 1.1, and bone lesion progression using Prostate Cancer Clinical Trials Working Group 3 criteria), health-related quality of life during carboplatin treatment using the Functional Assessment of Cancer Therapy-Prostate questionnaire and the European Organisation for Research and Treatment of Cancer questionnaire and safety profile of carboplatin (National Cancer Institute's Common Terminology Criteria for Adverse Events version 5.0)., Results: The trial started enrollment in September 2023. This trial is ongoing, and 12 patients have been recruited to date. All 49 participants will be enrolled according to plan., Conclusions: This prospective phase II trial represents a critical step toward addressing the therapeutic gap in patients with mCRPC harboring HRR pathway mutations, particularly in demographic regions with limited access to poly (ADP-ribose) polymerase inhibitors. Outcomes from this study will inform clinical practice and guide future phase III randomized trials, ultimately improving patient outcomes globally., Trial Registration: Clinical Trials Registry of India CTRI/2023/04/051507; https://ctri.nic.in/Clinicaltrials/pmaindet2.php?EncHid=Njc0NjU=&Enc=&userName=., International Registered Report Identifier (irrid): DERR1-10.2196/54086., (©Rishabh Jain, Akash Kumar, Atul Sharma, Ranjit Kumar Sahoo, Aparna Sharma, Amlesh Seth, Brusabhanu Nayak, Shamim A Shamim, Seema Kaushal, Haresh KP, Chandan J Das, Atul Batra. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 18.04.2024.)