Quiescent cancer cells resist T cell attack by forming an immunosuppressive niche.

Immunotherapy is a promising treatment for triple-negative breast cancer (TNBC), but patients relapse, highlighting the need to understand the mechanisms of resistance. We discovered that in primary breast cancer, tumor cells that resist T cell attack are quiescent. Quiescent cancer cells (QCCs) form clusters with reduced immune infiltration. They also display superior tumorigenic capacity and higher expression of chemotherapy resistance and stemness genes. We adapted single-cell RNA-sequencing with precise spatial resolution to profile infiltrating cells inside and outside the QCC niche. This transcriptomic analysis revealed hypoxia-induced programs and identified more exhausted T cells, tumor-protective fibroblasts, and dysfunctional dendritic cells inside clusters of QCCs. This uncovered differential phenotypes in infiltrating cells based on their intra-tumor location. Thus, QCCs constitute immunotherapy-resistant reservoirs by orchestrating a local hypoxic immune-suppressive milieu that blocks T cell function. Eliminating QCCs holds the promise to counteract immunotherapy resistance and prevent disease recurrence in TNBC.

Mutational analysis in different genes underlying severe combined immunodeficiency in seven consanguineous Pakistani families.

BACKGROUND: Severe Combined Immunodeficiency (SCID) is an autosomal recessive inborn error of immunity (IEI) characterized by recurrent chest and gastrointestinal (GI) infections and in some cases associated with life-threatening disorders. METHODOLOGY AND RESULTS: This current study aims to unwind the molecular etiology of SCID and also extended the patients' phenotype associated with identified particular variants. Herein, we present 06 disease-causing variants identified in 07 SCID-patients in three different SCID related genes. Whole Exome Sequencing (WES) followed by Sanger Sequencing was employed to explore genetic variations. The results included identification of two previously reported heterozygous variants in homozygous form for the first time in RAG1gene [(p.Arg410Gln);(p.Arg737His)], followed by a recurrent variant (p.Trp959*) in RAG1, a novel variant in IL2RG (p.Asp48Lfs*24), a recurrent variant in IL2RG (p.Gly271Glu) and a recurrent variant in DCLRE1C (p.Arg191*) gene. CONCLUSION: To conclude, the immune-profiling and WES revealed two novel, two as homozygous state for the first time, and two recurrent disease causing variants contributing valuably to our existing knowledge of SCID.

Obsession to fairness and topical steroid induced acne: A situation analysis of patients presenting in dermatology clinic at a private hospital in Karachi.

Objective: To determine the frequency of acne and other relevant side effects as well as the pattern of topical steroid and fairness cream use among patients presenting with steroid and fairness cream use at dermatology OPD in a tertiary care private hospital in Karachi. Methods: A cross-sectional survey was conducted from April, 2020 to December, 2020 in a private tertiary care hospital in Karachi. In total, 226 patients with a positive history of topical steroids and/or fairness creams use in the past six months were included in the study. Information was collected about sociodemographic characteristics; topical corticosteroid uses while clinical examination of facial skin was performed by a dermatologist. Data were analyzed using SPSS version-19. Results: The median age of study participants was 26 years with an interquartile range of 10 years. This frequency of corticosteroid induced acne was highest i.e., 83.6% (n=189) followed facial erythema and telangiectasia i.e., 50.9% (n=115) 47.8% (n=108) respectively. The estimated median duration of using topical steroids or fairness creams or both was six months with an IQR of four months. The study found statistically significant differences in the reasons of using topical corticosteroids or fairness creams on the face on the basis of differences in the level of education and marital status. Conclusion: In Karachi, both, men and women are equally obsessed with fair skin tone and use topical steroids and fairness cream. The use of corticosteroid or fairness cream-induced facial acne is alarmingly high among patients presenting in a dermatology clinic in Karachi.

Platinum-Chimeric Carrier Cells for Ultratrace Cell Analysis in Mass Cytometry.

Mass cytometry by time-of-flight (CyTOF), a high-dimensional single-cell analysis platform, detects up to 50 biomarkers at single-cell resolution. However, CyTOF analysis of biological samples with a minimal number of available cells or rare cell subsets remains a major technical challenge due to the extensive loss of cells during cell recovery, staining, and acquisition. Here, we introduce a platinum-chimeric carrier cell strategy for mass cytometry profiling of ultratrace cell samples. Cisplatin can rapidly enter broken plasma membranes of dead cells and form a chimeric interaction with cellular proteins, peptides, and amino acids. Thus, 198Pt-cisplatin is adopted to tag carrier cells in the pretreatment stage. We investigated 8 cell lines that are commonly accessible in laboratories for their potential as carrier cells to preserve rare target cells for CyTOF analysis. We designed a panel of 35 protein biomarkers to evaluate the comprehensive single-cell subtype classification capability with or without the carrier cell strategy. We further demonstrated the detection and analysis of as few as 1 × 104 immune cells using our method. The proposed method thus allows CyTOF analysis on precious clinical samples with less abundant cells.

Pairwise synthetic cytotoxicity between Paxlovid and 100 frequently prescribed FDA-approved small molecule drugs on liver cells.

Paxlovid is a recent FDA approved specific drug for COVID-19. Extensive prescription of Paxlovid could induce potential synthetic cytotoxicity with drugs. Herein, we aimed to examine pairwise synthetic cytotoxicity between Paxlovid and 100 frequently FDA approved small molecule drugs. Liver cell line HL-7702 or L02 was adopted to evaluate synthetic cytotoxicity between Paxlovid and the 100 small molecule drugs. Inhibitory concentration IC-10 and IC-50 doses for all the 100 small molecule drugs and Paxlovid were experimentally acquired. Then, pairwise synthetic cytotoxicity was examined with the fixed dose IC-10 for each drug. The most 4 significant interactive pairs (2 positively interactive and 2 negatively interactive) were further subjected to molecular docking simulation to reveal the structural modulation with Caspase-8, a key mediator for cell apoptosis.

Median Arcuate Ligament Syndrome: Comparing the Safety of Open and Laparoscopic Management in a Large Cohort.

BACKGROUND: Open surgery has been the traditional approach for Median Arcuate Ligament Syndrome (MALS) management. However, there has been a recent rise in laparoscopic management for MALS. In this study we used a large-scale database to compare perioperative complications between open and laparoscopic approaches for MALS. METHODS: Using the National Inpatient Sampling database, we identified all patients surgically treated for MALS between 2008 and 2018 through conventional open and laparoscopic approaches. International Classification of Diseases (ICD)-9 and ICD-10 codes were used to identify patients and their specific surgical interventions. Statistical analyses were conducted to compare the perioperative complications between the 2 MALS surgical approaches, as well as and length of hospital stays and total charges. The complications include postoperative bleeding, accidental operative laceration/puncture, surgical wound infection, ileus, hemothorax/pneumothorax, and cardiac and respiratory complications. RESULTS: A total of 630 patients were identified: 487 (77.3%) patients underwent open surgery while 143 (22.7%) patients underwent laparoscopic decompression. The majority of the study population consisted of female patients (74.8%) with a mean age of 40.6 ± 19 years. Patients who underwent laparoscopic decompression had significantly less all-cause perioperative complications compared to their open surgery counterparts (0.7% vs. 9.9%; P = 0.001). Additionally, prolonged hospitalization was noted in the open group compared to the laparoscopic 1 (5.8 days vs. 3.5; P < 0.001, respectively) with a significantly higher mean of total hospital charges ($70,095.8 vs. 56,113.5; P = 0.016). CONCLUSIONS: Laparoscopic management of MALS has significantly less perioperative complications than open surgical decompression with shorter hospitalization and lower total charges. Given that, laparoscopic technique could be a safe option in treating select MALS patients.

Adolescent boys' and girls' perspectives on social norms surrounding child marriage in Nepal.

According to recent data, in Nepal, 38.2% of women aged 20-24 years are married by the age of 18. This analysis of CARE's Tipping Point Initiative seeks to compare Nepali adolescent boys' and girls' perceptions of empirical and normative expectations around child, early and forced marriage. A baseline survey of 1,134 adolescent girls and 1,154 adolescent boys provided 11 items for descriptive quantitative analysis. Thirty in-depth interviews and 16 focus groups were conducted with young people aged 12-16 years and analysed using modified Grounded Theory. Themes in the data produced thick descriptions of gender roles/responsibilities, employment, mobility and marriage. Comparisons by gender of normative and empirical expectations, and sanctions on child, early and forced marriage were produced. Gender roles/responsibilities underpin social norms for mobility, marriage and employment, and are connected by subthemes with a focus on responsibility for household chores, interaction between unmarried adolescents, education/financial stability, honour/reputation, and parental decision-makers). Participants agreed on gendered labour, women's employment, and parents as decision-makers. Areas of disagreement included repercussions for interactions between unmarried adolescents, girls' mobility, attributes of the ideal woman, and maintaining family honour. Programming recommendations include focusing on the inter-relatedness of boys' and girls' wellbeing, communication between girls and parents, and structural support for education Research recommendations include identifying factors underlying sexual harassment and constructs of masculinity and femininity.

Guanosine and Deoxyinosine Structural Analogs Extracted from Chick Early Amniotic Fluid Promote Cutaneous Wound Healing.

Wound healing is a complex, dynamic process supported by a myriad of cellular events that must be tightly coordinated to efficiently repair damaged tissue. These wounds are a significant socioeconomic burden due to their high prevalence and recurrence, which is why the phenomenon of wounds has also been labeled as a "Silent Epidemic". Most of these wounds become "chronic", with around 15% of them remaining unresolved 1-year post incidence, which results in a prolonged yet avoidable burden to patients, families, and the health system. In this experimental study, we tried to purify the potent components in chick early amniotic fluid (ceAF) and applied these components to the wound healing mechanism. We first subjected ceAF to a series of purifications, including an HPLC purification system along with ion-exchange chromatography technology to purify other potential components. Upon narrowing down, we found two structural analogs: guanosine and deoxyinosine. We performed these components' cell scratch and trans-well migration assays to validate the accurate dosage. We also assessed these components via topical administration on the skin of murine model wounds. For this, we randomly divided C57BL/6 (all black, male, 5 weeks old) mice into groups. The wound model was established through excising the skin of mice and treated the wounds with different fractions of guanosine and deoxyinosine continuously for 8-10 day intervals. Once the healing was complete, the skin was excised to determine the inflammatory response and other biochemical parameters of the healed skin, including epidermal thickness, collagen density, macrophages, and neutrophil infiltration at the wounded site. Quantitative real-time PCR and immunoblot assays were performed to determine active gene expression and protein expression of proinflammatory molecules, growth factors, and cytokines. All these findings support our data indicating the promising healing properties of guanosine and deoxyinosine isolated from ceAF.

Sickle-like Inertial Microfluidic System for Online Rare Cell Separation and Tandem Label-Free Quantitative Proteomics (Orcs-Proteomics).

Label-free proteomics with trace clinical samples provides a wealth of actionable insights for personalized medicine. Clinically acquired primary cells, such as circulating tumor cells (CTCs), are usually with low abundance that is prohibitive for conventional label-free proteomics analysis. Here, we present a sickle-like inertial microfluidic system for online rare cell separation and tandem label-free proteomics (namely, Orcs-proteomics). Orcs-proteomics adopts a buffer system with 0.1% N-dodecyl ß-d-maltoside (DDM), 1 mM Tris (2-carboxyethyl) phosphine (TCEP), and 2 mM 2-chloroacetamide (CAA) for cell lysis and reductive alkylation. We demonstrate the application of Orcs-proteomics with 293T cells and manage to identify 913, 1563, 2271, and 2770 protein groups with 4, 13, 68, and 119 cells, respectively. We then spike MCF7 cells with white blood cells (WBCs) to simulate the patient's blood sample. Orcs-proteomics identifies more than 2000 protein groups with an average of 61 MCF7 cells. We further recruit two advanced breast cancer patients and collect 5 and 7 CTCs from each patient through minimally invasive blood drawing. Orcs-proteomics manages to identify 973 and 1135 protein groups for each patient. Therefore, Orcs-proteomics empowers rare cells simultaneously to be separated and counted for proteomics and provides technical support for personalized treatment decision making with rare primary patient samples.

Global measurement of intimate partner violence to monitor Sustainable Development Goal 5.

BACKGROUND: One third of women experience intimate partner violence (IPV) and potential sequelae. Sustainable Development Goal (SDG) 5.2-to eliminate violence against women, including IPV-compels states to monitor such violence. We conducted the first global measurement-invariance assessment of standardised item sets for IPV. METHODS: Demographic and Health Surveys (DHS) from 36 Lower-/Middle-Income Countries (LMICs) administering 18 IPV items during 2012-2018 were included. Analyses were performed separately for two items sets: lifetime physical IPV (seven items) and controlling behaviours (five items). We performed country-specific exploratory and confirmatory factor analyses (EFA/CFA). Datasets meeting benchmarks for acceptable item loadings and model-fit statistics were included in multiple-group CFA (MGCFA) to test for exact measurement invariance. Based on findings, alignment optimization (AO) was performed to assess approximate measurement invariance (< 25% of model parameters non-invariant). For each item set, national rankings based on AO-derived scores and on prevalence estimates were compared. AO-derived scores were correlated with type-specific IPV prevalences to assess correspondence. RESULTS: National rates of physical IPV (5.6-50.5%) and controlling behavior (25.9-84.7%) varied. For each item set, item loadings and model-fit statistics were adequate in country-specific, unidimensional EFAs and CFAs. Both unidimensional constructs lacked exact invariance in MGCFA but achieved approximate invariance in AO analysis (12.3% of model parameters for physical IPV and 6.7% for controlling behaviour non-invariant). For both item sets, national rankings based on AO-derived scores were distributed similarly to rankings based on prevalence. However, estimates often were not significantly different cross-nationally, precluding national-level comparisons regardless of estimation strategy. Three physical-IPV items (slap, twist, choke) and two controlling-behaviour items (meet female friends; contact with family) warrant cognitive testing to improve their psychometric properties. Correlations of AO-derived scores for physical IPV (0.48-0.66) and controlling behaviours (0.49-0.87) with prevalences of lifetime physical, sexual, psychological IPV as well as controlling behaviour varied. CONCLUSIONS: Seven DHS lifetime physical-IPV items and five DHS controlling-behaviour items were approximately invariant across 36 LMICs spanning five world regions, such that cross-national comparisons of factor means are reasonable. Measurement-invariance testing over time will inform their utility to monitor SDG5.2.1; cross-national, cross-time measurement-invariance testing of improved sexual and psychological IPV item-sets is needed.

PrEParing for long-acting injectable PrEP in the South: perspectives from healthcare providers in Georgia.

New modalities of Pre-exposure Prophylaxis (PrEP) such as long-acting injectable PrEP (LAI-PrEP) promise increased prevention of HIV transmission; however, similar biomedical interventions have not been met with universal adoption by healthcare providers or populations most affected by HIV. This qualitative study explores healthcare provider considerations for the rollout of LAI-PrEP. Eleven key-informant in-depth interviews were conducted with clinicians who prescribe daily oral PrEP. Participants reviewed a currently proposed LAI regimen and were asked to reflect on its implications for their clinical practice. Interviews were transcribed verbatim and thematically coded, with results organized using the Consolidated Framework for Implementation Research (CFIR). All participants expressed interest in prescribing LAI-PrEP and anticipated that at least some patients would be interested. Participants identified characteristics of the intervention, inner intervention setting, and outer intervention setting that will be influential in bringing LAI-PrEP to scale. Clinicians in the South have unique insights into the challenges of and opportunities for successful rollout of future PrEP regimens. Bringing these insights into a CFIR framework highlights the nuances surrounding LAI-PrEP, including structural concerns such as cost barriers and access to in-person healthcare services. It is critical to address these challenges to ensure successful implementation of new PrEP formulations.

Prevalence of Fibromyalgia in chronic kidney disease pre-dialysis patients: Experience from a Tertiary Care Renal unit in Pakistan.

BACKGROUND AND OBJECTIVE: Fibromyalgia syndrome (FMS) is a well-established medical problem which gives rise pain at various sites, fatigue, sleep disturbances, poor memory and definitely affects quality of life. Its prevalence in chronic kidney disease (CKD) is scarcely reported, thus we aimed to assess this condition and report its prevalence in our population. METHODS: The current study was carried out in all adult CKD stage III and IV patients registered from January 2020 to July 2020 at outpatient department of a tertiary care renal institution in Karachi, Pakistan. This is a cross sectional study where prevalence of FMS was assessed by interviewing and examining patients according to established criteria for FMS. All data and laboratory parameters were recorded on a proforma and statistical analysis was done on SPSS version22.0. RESULTS: During the study period of six months, 161 patients with CKD stage III and IV were registered. Among these 81 male and 80 were females. Mean age was 47.12±9.27 (range 21-60) years. There were 22 (13.66%) patients found to have FMS. Mean Widespread Pain Index (WPI) score was 5.68±4.36 (range 1-16), while severity scale (SS) 2a was 3.17±1.78 (range 1-9) and SS2b 2.04±0.96 (range 1-5) was recorded. CONCLUSION: From Pakistan prevalence of FMS has never been published. As this syndrome affects quality of life of patients, its recognition and proper management is immensely required.

Label-free Separation of Circulating Tumor Cells Using a Self-Amplified Inertial Focusing (SAIF) Microfluidic Chip.

Circulating tumor cells (CTCs) are rare cells existing in the bloodstream with a relatively low number, which facilitate as a predictor of cancer progress. However, it is difficult to obtain highly purified intact CTCs with desired viability due to the low percentage of CTCs among blood cells. In this work, we demonstrate a novel self-amplified inertial focused (SAIF) microfluidic chip that enables size-based, high-throughput, label-free separation of CTCs from a patient's blood. The SAIF chip introduced in this study demonstrated the feasibility of an extremely narrow zigzag channel (with 40 µm channel width) connected with two expansion regions to effectively separate different-sized cells with amplified separation distance. The chip performance was optimized with different-sized polystyrene (PS) particles and blood cells spiked with three different types of cancer cells. The separation efficiencies for blood cells and spiked cancer cells are higher than 80%. Recovery rates of cancer cells were tested by spiking 1500 lung cancer cells (A549), breast cancer cells (MCF-7), and cervical cancer cells (HeLa) separately to 3 mL 0.09% saline with 3 × 106 white blood cells (WBCs). The recovery rates for larger cells (MCF-7 and HeLa) were 79.1 and 85.4%, respectively. Viabilities of the cells harvested from outlets were all higher than 97% after culturing for 24, 48, and 72 h. The SAIF chip performance was further confirmed using the real clinical patient blood samples from four lung cancer patients. Theoretical force balance analysis in physics, computational simulations, and experimental observations indicate that the SAIF chip is simple but effective, and high-throughput separation CTCs can be readily achieved without complex structures.

Peripubertal gonadal steroids are necessary for steroid-independent male sexual behavior in castrated B6D2F1 male mice.

Gonadal steroids play an integral role in male sexual behavior, and in most rodent models, this relationship is tightly coupled. However, many other species, including humans, continue to demonstrate male sex behavior in the absence of gonadal steroids, and the mechanisms that regulate steroid-independent male sex behavior are not well understood. Approximately 30% of castrated male B6D2F1 hybrid mice display male sex behavior many months after castration, allowing for the investigation of individual variation in steroidal regulation of male sex behavior. During both the perinatal and peripubertal periods of development, the organizational effects of gonadal steroids on sexual differentiation of the neural circuits controlling male sex behavior are well-documented. Several factors can alter the normal range of gonadal steroids or their receptors which may lead to the disruption of the normal processes of masculinization and defeminization. It is unknown whether the organizational effects of gonadal hormones during puberty are necessary for steroid-independent male sex behavior. However, gonadal steroids during puberty were not necessary for either testosterone or estradiol to activate male sex behavior in adulthood. Furthermore, activation of male sex behavior was initiated sooner in hybrid male mice castrated prior to puberty that were administered estradiol in adulthood compared to those that were provided testosterone. The underlying mechanisms by which gonadal hormones, during both the perinatal and peripubertal developmental periods of sexual differentiation, organize the normal maturation of neural circuitry that regulates steroid-independent male sex behavior in adult castrated B6D2F1 male mice warrants further investigation.

An investigation of the relationship between autonomy, childbirth practices, and obstetric fistula among women in rural Lilongwe District, Malawi.

BACKGROUND: Obstetric fistula is a childbirth injury caused by prolonged obstructed labor that results in destruction of the tissue wall between the vagina and bladder. Although obstetric fistula is directly caused by prolonged obstructed labor, many other factors indirectly increase fistula risk. Some research suggests that many women in rural Malawi have limited autonomy and decision-making power in their households. We hypothesize that women's limited autonomy may play a role in reinforcing childbirth practices that increase the risk of obstetric fistula in this setting by hindering access to emergency care and further prolonging obstructed labor. METHODS: A medical student at Baylor College of Medicine partnered with a Malawian research assistant in July 2015 to conduct in-depth qualitative interviews in Chichewa with 25 women living within the McGuire Wellness Centre's catchment area (rural Central Lilongwe District) who had received obstetric fistula repair surgery. RESULTS: This study assessed whether women's limited autonomy in rural Malawi reinforces childbearing practices that increase risk of obstetric fistula. We considered four dimensions of autonomy: sexual and reproductive decision-making, decision-making related to healthcare utilization, freedom of movement, and discretion over earned income. We found that participants had limited autonomy in these domains. For example, many women felt pressured by their husbands, families, and communities to become pregnant within three months of marriage; women often needed to seek permission from their husbands before leaving their homes to visit the clinic; and women were frequently prevented from delivering at the hospital by older women in the community. CONCLUSIONS: Many of the obstetric fistula patients in our sample had limited autonomy in several or all of the aforementioned domains, and their limited autonomy often led both directly and indirectly to an increased risk of prolonged labor and fistula. Reducing the prevalence of fistula in Malawi requires a broad understanding of the causes of fistula, so we recommend that the relationship between women's autonomy and fistula risk undergo further investigation.

A lack of sociodemographic participant diversity in endometriosis evidence risks unrepresentative clinical guidance: a structured review of the evidence contributing to a NICE guideline.

BACKGROUND: Women who are black are less likely to be diagnosed with endometriosis than white women. There is no confirmed biological basis, so this likely represents structural barriers around health care. There is a lack of evidence exploring the interface between ethnicity and symptoms or experience of care and treatment. AIM: To map recording of sociodemographic diversity in the evidence informing an endometriosis guideline. METHOD: Inclusion of study setting, ethnicity, age, and socioeconomic status was documented within the evidence cited in National Institute for Health and Care Excellence (NICE) NG73 (2017) Endometriosis diagnosis and management. Included were 44 studies with 43 sample groups from the chapters: 'Signs and Symptoms', 'Information and Support', and 'Diagnosis'. Data were extracted independently by two researchers. RESULTS: No studies were conducted in primary care. The evidence cited in 'Signs and Symptoms' and 'Diagnosis' was exclusively from tertiary care. 'Information and Support' included 9/16 studies from tertiary care, and 7/16 recruited through community and advocacy networks. For ethnicity, 4/44 studies formally reported participant ethnicity (three from 'Information and Support', one from 'Diagnosis'). In these, 93%, 90%, 60%, and 75% of participants were white/Caucasian (mean 79.5%). For age, 3/44 studies included adolescents. Many studies excluded women who were deemed outside reproductive age. For socioeconomic status, eight studies, all from 'Information and Support', reported socioeconomic status in some form. The majority of participants were tertiary educated. CONCLUSION: These results highlight the missing demographics within evidence cited in a national guideline for endometriosis. These align with documented inequities in diagnosis of endometriosis and warrant urgent attention.

Investigating the association of Angiotensin II Type I Receptor A1166C Polymorphism with Breast Cancer Risk in the Pakistani Population.

The polymorphisms of the Renin-Angiotensin System are related to many disorders like diabetes, cardiovascular disease, and different types of cancer. Among all the polymorphisms related to AGTR1, A1166C has been associated with several disorders, including cardiovascular diseases and breast cancer. This study was conducted to discover the association of AGTR1 polymorphism (A1166C) Renin-Angiotensin and its effect on the development and progression of breast cancer in the Pakistani population. One hundred forty participants, including seventy diagnosed breast cancer patients and seventy healthy individuals, were included in this study and genotyped with an allele-specific polymerase chain reaction. The most frequent genotype in healthy participants and breast cancer patients was CC. An insignificant (p value>0.05) risk of breast cancer was found with A1166C polymorphism in codominant (CC vs. AA OR=1.200 [0.256-5.631] and AC vs. AA 0.941 [OR=0.223-3.976]), dominant (OR=1.00 [0.240-4.167]), recessive (OR=1.230 [0.593-2.552]) and additive models (OR=1.028 [0.533-1.983]) of general population genotypes. Nonetheless, when the AA genotype was considered a reference group, a significant association was found between AC and CC genotypes and invasive ductal and ductal carcinoma development in breast cancer patients. In conclusion, this study demonstrated no significant association between AGTR1 (A1166C) polymorphism and breast cancer risk.

Systematic Review of the Global Literature on Uncomplicated Recurrent Urinary Tract Infections in Women: Underscoring Major Heterogeneity.

OBJECTIVE: To examine the global literature database on uncomplicated recurrent urinary tract infections (rUTI), this systematic review assesses the availability of rUTI data based on geographic region and elucidates the current state of research and gaps in knowledge. METHODS: The databases PubMed, Embase, WHO Global Index Medicus, and SciELO were searched for keywords related to rUTI between 2000 and 2023. Three independent reviewers screened studies restricted to female participants age ≥18 years with uncomplicated rUTIs. Studies were excluded if they did not provide a definition for rUTI or did not cite or report an estimate for rUTI prevalence. The review was registered in PROSPERO and conformed to PRISMA guidelines. RESULTS: The search yielded 2947 studies of which 124 were ultimately included. Convenience samples were used for 91% of studies and sample sizes were 30% n <50, 29% n = 50-99, 22% n = 100-199, 36% n ≥200. Most studies were conducted in Europe (41%) or North America (39%), were prospective (52%), at tertiary centers (49%) and included all ages ≥18 (60%). The most common definition for rUTI was 2 UTI/6 m or 3 UTI/1y (62%). Regardless of study location, most studies cited prevalence estimates for rUTI derived from U.S.-based populations. CONCLUSION: This study represents the first formal investigation of the global literature base on uncomplicated rUTI. Studies on rUTIs are globally of small scale and definitions used for rUTI are heterogeneous. More studies are needed to ascertain the true prevalence of rUTI outside of North America and Europe.

Time-lapse proteomics unveil constant high exposure of non-antibiotic drug induces synthetic susceptibility towards regular antibiotics.

Antibiotic resistance is a significant threat to the human race, as regular consumption of antibiotics may lead to antibiotic-resistant bacterial strains. Non-antibiotic drugs also have an extensive impact on bacterial strains, where persistent uptake alters the survival mechanisms of bacteria that could lead to cross-resistance towards other antibiotics. Here, we use time-lapse proteomics shift assays to examine Gram-negative (E. coli. O157:H7 and P. aeruginosa) and Gram-positive (E. faecalis and S. aureus) strains of bacteria for short and continuous exposure to the non-antibiotic drug Hydroxychloroquine (HCQ). Proteomic transitions from wild type to HCQ-exposed strains revealed bacterial transitions and their survival adaptabilities, which were different across all strains. In addition to their structural differences, some shared pathways were enriched among Gram-negative and positive strains. We also validated the cross-resistance and sensitivity towards 24 regularly prescribed antibiotics, indicating that long-term exposure to non-antibiotic drugs may induce general proteomics alterations in the bacterial strains, promoting antibiotic resistance. We validated that HCQ exposure renders Gram-negative strains resistant to Β-lactam and susceptible to macrolides and folic acid. In contrast, Gram-positive strains become susceptible to Β-lactam and resistant to aminoglycosides. Exposure to non-antibiotic drugs causes resistance or susceptibility toward other antibiotics, providing clinicians a reason to overcome antibiotic resistance.