OBJECTIVE:To evaluate the recurrence of cervical intraepithelial neoplasia grade 2 or worse or carcinoma (CIN2+) after conization by post-treatment human papillomavirus (HPV) genotype, timing of HPV detection, and cone margin status. MATERIALS AND METHODS:We analyzed a retrospective cohort of unvaccinated women treated by conization for CIN2+ or carcinoma (2010-2024) with HPV genotyping performed more than 4 months after excision. Results were categorized as HPV16, HPV18, another 12 high-risk types pooled (hrHPV), or negative, and as early (4-12 mo) or late (>12 mo) after conization. Recurrence was histologically confirmed, and adjusted incidence rate ratios (aIRRs) were estimated using Poisson regression. RESULTS:Among 2,628 women with genotyping, early HPV16 detection had the highest CIN2+ recurrence rate, 294 per 1,000 person-years (py). Compared with early HPV16, recurrence was lower among women with the other 12 hrHPV types pooled (34 per 1,000 py; aIRR: 0.13; 95% CI: 0.06-0.26) and among those with HPV-negative results (2 per 1,000 py; aIRR: 0.01; 95% CI: 0.00-0.02). With late detection, recurrence remained highest among women with HPV16 positivity (321 cases per 1,000 py), whereas the recurrence rate associated with the pooled other 12 hrHPV genotypes was twice as high as that observed with early detection (74 cases per 1,000 py). Positive margins were associated with higher recurrence risk, primarily among women with early post-excision HPV positivity. CONCLUSIONS:Post-treatment HPV genotyping reveals marked heterogeneity in CIN2+ recurrence risk. This pattern may improve risk-stratified screening and may help interpret recurrence reductions reported after HPV16-containing vaccination.
OBJECTIVES/PURPOSES OF THE STUDY:This study aimed to describe and evaluate the feasibility and technical considerations of a modified loop electrosurgical excision procedure (LEEP) employing Foley catheter traction to enhance cervical stabilization and specimen integrity during excision. METHODS:This single-center retrospective feasibility study included patients who underwent LEEP for cervical dysplasia between January 2019 and November 2024. Patients treated using the modified LEEP technique constituted the feasibility group. A descriptive comparator group consisted of patients who underwent standard LEEP during the same period. Perioperative, pathologic, and postoperative outcomes were analyzed. RESULTS:A total of 123 patients underwent LEEP during the study period, of whom 108 met the inclusion criteria. No specimen fragmentation was observed in the modified technique group, whereas a small number of fragmented specimens occurred in the standard technique group. Margin positivity rates and postoperative outcomes appeared comparable between groups. The study was not designed or powered for formal comparative inference. CONCLUSIONS:The modified LEEP technique employing Foley catheter traction appears feasible and reproducible, with favorable technical characteristics related to cervical stabilization and specimen handling. These findings are hypothesis-generating and support the need for prospective studies to further evaluate this technique in routine clinical practice.
OBJECTIVE:Preventive strategies for bacterial vaginosis (BV) include sexual partner treatment, short-term consolidation therapy, and long-term maintenance interventions. This systematic review and network meta-analysis (NMA) compares the efficacy of these approaches and evaluates effect modification by baseline recurrence risk. PATIENTS AND METHODS:Randomized-controlled trials (from inception to January 31, 2026) evaluating interventions to prevent BV recurrence in nonpregnant women were categorized into 3 analyses: partner treatment (pairwise meta-analysis), consolidation therapy, and long-term prevention (random-effects NMA). Certainty of evidence was evaluated using GRADE and CINeMA. RESULTS:Partner treatment significantly reduced BV recurrence rates [incident rate ratio (IRR) =0.76, 95% CI=0.60-0.98; moderate-certainty evidence] compared with placebo/no treatment. In consolidation therapy, acidifying agents [risk ratio (RR)=0.22, 95% CI=0.08-0.62; moderate-certainty evidence], vaginal probiotics (RR=0.37, 95% CI=0.15-0.93; moderate-certainty evidence), and oral probiotics (RR=0.45, 95% CI=0.21-0.96; low-certainty evidence) reduced early recurrence or persistence compared with placebo. In long-term prevention, vaginal probiotics were the only intervention achieving statistical significance overall (IRR=0.74, 95% CI=0.58-0.96; moderate-certainty evidence). Among women at low baseline risk, oral probiotics (IRR = 0.49, 95% CI=0.28-0.85) and acidifying agents (IRR=0.48, 95% CI=0.24-0.96) were most effective. Among women at high baseline risk, vaginal probiotics (IRR=0.70, 95% CI=0.52-0.93) and intermittent antibiotic suppression (IRR=0.39, 95% CI=0.21-0.73) showed the greatest reduction in recurrence. CONCLUSIONS:Partner treatment, consolidation with probiotics or acidifying agents, and long-term vaginal probiotic maintenance reduce BV recurrence. Vaginal Lactobacillus preparations and acidifying agents represent the most evidence-supported nonantibiotic approaches for recurrence prevention.
Objective: Population-based data on extended HPV genotyping for risk stratification in routine cervical cancer screening are limited. We evaluated the association between oncogenic risk categories derived from extended HPV genotyping and cervical screening outcomes (cytology and histology) in a large population-based cohort (October 2021-September 2023). Methods: This retrospective observational study analyzed HPV results and corresponding cytology and histology from screened women between October 2021 and September 2023. High-risk HPV genotypes were classified into three mutually exclusive categories: high (HOT), moderate (MOT), and low (LOT), developed for the organizational framework of this particular study. Cytologic and histologic outcomes were compared across categories using chi-square tests, and PPVs for CIN2+ and CIN3+ were calculated. Results: Among 448,394 screened women, overall HPV prevalence was 8.6%. HOT, MOT, and LOT genotypes accounted for 35.5%, 24.0%, and 40.5% of HPV-positive infections, respectively. Cytologic severity differed significantly across oncogenic risk categories ( p <.0001), with HOT genotypes contributing disproportionately to high-grade cytologic abnormalities. Histologic follow-up demonstrated marked differences in disease severity, with HOT genotypes accounting for 68.8% of CIN3+ diagnoses compared with 19.7% for MOT and 11.5% for LOT. Genotype-specific PPVs were highest for HPV16 and HPV31; category-level CIN3+ PPV was 23.0% for HOT, 14.6% for MOT, and 5.5% for LOT. Conclusions: Extended HPV genotyping was associated with a clear gradient of oncogenic risk; women with low-oncogenic risk infections demonstrated markedly lower rates of high-grade disease, supporting risk-stratified clinical management in cervical cancer screening programs.
OBJECTIVE:Cervical cancer, primarily caused by human papillomavirus (HPV) infection, is commonly detected using polymerase chain reaction (PCR)-based assays. However, these methods are time-consuming and require specialized instrumentation. This study evaluated the diagnostic performance of the loop-mediated isothermal amplification (LAMP) assay as a rapid alternative for HPV detection compared with conventional PCR testing. METHODS:This study included 933 nonpregnant women aged ≥19 years who underwent HPV testing for cervical cancer screening or follow-up. The HPV panel included 14 high-risk types (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68). Cervical swab samples underwent nucleic acid extraction followed by LAMP amplification using type-specific primers. Reactions were performed at 63 °C for 35 minutes, and results were interpreted colorimetrically (blue for positive, purple for negative). RESULTS:Compared with PCR, the LAMP assay showed a sensitivity of 97.8% (95% CI: 94.4-100.0) for HPV types 16 and 18 and 100.0% (95% CI: 98.8-100.0) for the remaining high-risk types. Specificity across all types was 100.0% (95% CI: 98.8-100.0). The overall diagnostic accuracy was 99.5% (95% CI: 99.0-100.0). When all 14 HPV types were analyzed collectively, clinical sensitivity and specificity were 99.4% and 100.0%, respectively. CONCLUSIONS:The LAMP assay provides a rapid, simple, and accurate method for HPV detection and may serve as a useful point-of-care screening tool, particularly in resource-limited settings.
OBJECTIVES:To describe clinician perspectives, priorities, and concerns regarding the development of a shared care model for long-term management of stable vulvar lichen sclerosus (VLS). METHODS:A cross-sectional online survey was conducted of clinicians involved in managing VLS. Stable VLS was defined as controlled disease on maintenance topical corticosteroids, ≤5 self-managed flares per year, patient acceptance of chronic therapy, no history of neoplasia, and no vulvar biopsy within the preceding 12 months. Survey items assessed current models of long-term care, perceived need for expanded community-based follow-up, barriers to shared care, and views on the appropriateness and requirements for successful implementation. Quantitative data were analyzed descriptively, and free-text responses underwent thematic analysis. Ethics approval was obtained. RESULTS:A total of 120 clinicians from 12 countries completed the survey, with 44.2% based in Australia. Respondents were predominantly gynecologists (51.3%) and dermatologists (27.7%), with most (68.1%) having more than 10 years' experience managing VLS. Overall, 85.1% supported a shared care model, with 68.4% rating it very appropriate, and 16.7% somewhat appropriate. Major barriers related to primary care included time and resource pressures, limited VLS knowledge, and inconsistent genital examination. Barriers identified in the specialist setting included patient preference for specialist-led care, concerns about the ability of other providers to titrate topical steroids, difficulty re-accessing specialist-led care, and communication or documentation gaps. CONCLUSION:Vulvar specialists internationally support shared care for stable VLS, yet formal models remain rare. The barriers are largely structural and modifiable, underscoring the need for operationalized shared care frameworks.
OBJECTIVE:To systematically evaluate the diagnostic performance of miRNA panels for endometrial cancer. METHODS:PubMed, Web of Science, CNKI, Embase, and VIP were searched for eligible studies published through 2025. Study quality was assessed using QUADAS-2. Pooled sensitivity, specificity, diagnostic odds ratio (DOR), and the area under the summary receiver operating characteristic curve (AUC) were calculated using Meta-Disc 1.4, Review Manager 5.3, and Stata 17.0. RESULTS:Nine primary studies involving 531 participants and 9 independent diagnostic models were included. The pooled diagnostic score was 4.78 (95% CI: 3.86-5.71), and the pooled DOR was 119.50 (95% CI: 47.49-300.70). The pooled sensitivity and specificity were 0.90 (95% CI: 0.81-0.95) and 0.93 (95% CI: 0.89-0.96), respectively. The AUC was 0.94 (95% CI: 0.92-0.96). Subgroup analyses indicated that geographic region and sample type might contribute to heterogeneity. CONCLUSION:miRNA panels show good diagnostic accuracy for endometrial cancer, with high sensitivity, specificity, and overall discriminatory ability. However, substantial heterogeneity and methodological limitations require cautious interpretation, and further large-scale prospective studies are needed before routine clinical application.
OBJECTIVES:To compare diagnostic strategies for detecting HSIL or worse (HSIL+) in women with high-grade cytology and negative colposcopy, and to assess whether sequential HPV testing, liquid-based cytology (LBC), and endocervical sampling improve diagnostic safety. METHODS:This is a multicenter randomized clinical trial conducted at 4 referral centers between 2021 and 2022. Women with ASC-H or worse cytology and negative colposcopy underwent HPV testing and LBC. Participants were randomized to endocervical brushing (EB) or endocervical curettage (ECC). The reference standard was histopathology from excisional procedures or structured follow-up. Diagnostic performance (sensitivity, specificity, predictive values, and accuracy) was calculated for individual tests and predefined combinations (AND ALL and MAJORITY rules). Absolute differences between strategies were analyzed. Invalid results were classified as failures (false negatives or false positives) according to the final diagnosis. RESULTS:Among 257 women, 35 cases of HSIL+ were identified. HPV testing showed the highest sensitivity (94.3%) and negative predictive value (98.6%), whereas LBC demonstrated higher specificity (84.9%) and accuracy (84.1%). The combination of HPV and LBC (AND rule) improved specificity to 91.7% with a sensitivity of 77.1%. Adding EB (MAJORITY rule) increased sensitivity to 100% (absolute increase 22.9%) but reduced specificity to 82.3%. ECC showed lower sensitivity (61.1%) and higher inadequacy rates (21.3%). CONCLUSIONS:In women with high-grade cytology and negative colposcopy, HPV testing followed by LBC provides a balanced diagnostic strategy. The addition of endocervical brushing may increase sensitivity in selected high-risk cases and improve the detection of HSIL+ after negative colposcopy.
OBJECTIVES:Mixed vaginitis (MV) and the co-occurrence of bacterial vaginosis (BV) and vaginal Candida spp. remain insufficiently defined. This study aimed to compare the clinical and microbiological characteristics of women with BV alone and those with concomitant BV and morphologic evidence of Candida infection. METHODS:This cross-sectional study, conducted in accordance with the STROBE guidelines, evaluated women diagnosed using Gram-stained smears and liquid-based cytology: 118 patients with BV alone based on Nugent criteria; and 65 patients with MV (BV based on Nugent criteria and Candida species). RESULTS:Women in the BV group were more frequently asymptomatic [55.1% (65/118) vs. 26.2% (17/65); p=.0001]. Normal colposcopic results were observed more frequently in the BV group [99/118 (83.9%) vs. 17/65 (26.2%); p=.0001]. Women in the MV group more commonly reported discharge with itching [21/65 (32.2%) vs. 4/118 (3.4%); p=.0001] and exhibited a significantly higher prevalence of colpitis [47/65 (72.3%) vs. 10/118 (8.5%); p=.0001). Megasphaera type 1 [99/118 (83.9%)], Mobiluncus spp. [49/118 (41.5%)], and BV-associated bacteria (BVAB2) [86/118 (72.9%)] were more frequently observed in the BV group (p<.05), while a higher prevalence of lactobacilli was noted in the MV group (58.5%; p<.05). Candida albicans was predominant in the MV group (89%). CONCLUSIONS:MV was associated with pruritus, vaginal discharge, and colpitis, whereas BV was more often asymptomatic and associated with specific anaerobic bacteria. Both lactobacilli and anaerobes are often present in MV, with C. albicans being the most common fungus.
OBJECTIVES:We evaluated agreement between human papillomavirus (HPV) tests performed on self-collected vaginal and clinician-collected cervical specimens to advance HPV self-collection as a cervical cancer screening option in our health care system. METHODS:This diagnostic accuracy study was conducted at an academic medical center. Participants were 25-65 years old with upcoming colposcopy appointments. One cohort (n = 79) self-collected a vaginal specimen in the clinic immediately before a clinician-collected cervical specimen. The second cohort (n = 115) self-collected a vaginal specimen at home, mailed it in, and had a clinician-collected cervical specimen in the clinic. Paired specimens were evaluated for total (TPA), positive (PPA), and negative (NPA) percentage agreement. Extreme temperature stability studies were also conducted. RESULTS:Compared with clinician-collected cervical specimens, in-clinic self-collected vaginal specimens showed a TPA, PPA, and NPA of 98%, 100%, and 97% for HPV16; 99%, 100%, and 99% for HPV18; 86%, 94%, and 79% for high-risk other (HRO) HPV. The TPA, PPA, and NPA for at-home self-collected vaginal specimens compared with clinician-collected cervical specimens were 94%, 79%, and 96% for HPV16; 95%, 43%, and 98% for HPV18; 89%, 80%, and 93% for HRO. Vaginal specimens showed prolonged stability and were unaffected by extreme temperatures. CONCLUSIONS:In general, in-clinic and at-home self-collected vaginal HPV specimens for HPV screening demonstrate high agreement with clinician-collected cervical specimens, with the exception of low PPA in the at-home self-collected vaginal HPV18 subgroup. Our findings support the use of HPV self-collection as a practical option to expand access to cervical cancer screening.
OBJECTIVES:To evaluate the prevalence of mood disorder symptoms and measure the quality of life in women with vulvar dermatoses attending a specialized vulvar clinic in southern Sweden. METHODS:A questionnaire-based study among consecutive women attending the vulvar unit at the Department of Dermatology and Venereology at Skåne University Hospital. Sociodemographic factors were collected; depression and anxiety were assessed with the Hospital Anxiety and Depression Scale (HADS) and health-related quality of life with the EQ-5D VAS. RESULTS:In all, 217 of 242 women participated (response rate 90%). Data was collected from March 2020 to January 2023. The largest diagnostic group was lichen sclerosus (62%), followed by lichen planus (9.2%) and pain disorders (5.5%). Symptoms of depression and anxiety were highest among women with pain disorders (n=12, anxiety symptoms 58.3%, depression symptoms 20%), followed by Candida vulvovaginitis (n=7, anxiety symptoms 57.2%, depression symptoms 0.0%) and pruritus vulvae (n=7, anxiety symptoms 42.9% and depression symptoms14.3%). Differences between these groups were not significant. The mean EQ-5D VAS score was 69.7±19.7. CONCLUSIONS:Women with pain disorders, Candida vulvovaginitis, and pruritus vulvae showed the highest levels of mood symptoms. These findings support the importance of assessing mood symptoms and quality of life in the management of women with vulvar disease.
This study investigates obstetrics and gynecology (OB/GYN) residents' attitudes and practices towards human papillomavirus (HPV) prevention. OB/GYN residents nationwide received an online survey. One hundred sixty-one residents (89.4% females) participated. About 90.0% received the HPV vaccine, mostly before age 26. About 95.1% completed the series. Mean age and sex were significantly associated with vaccination status ( p < .001). Perceived occupational risk of HPV exposure was considered low in 52.2%, high in 45.3%, and absent in 2.5%. During loop electrosurgical excision procedures (LEEP), 27.92% reported always wearing an N95 mask, while 22.73% never do. Reassuringly, most OB/GYN residents are vaccinated against HPV. However, further improvement of protection against HPV (both vaccination and use of personal protective equipment) is recommended, as only 27.9% report always wearing an N95 mask during LEEP.
OBJECTIVE:This study evaluated the clinical performance of vaginal specimens collected using a new self-collection device and a well-established self-collection device, compared with cervical specimens collected by clinicians for HPV detection. METHODS:A total of 1,763 women undergoing routine cervical screening or referred to colposcopy provided self-collected vaginal specimens, using simpli-COLLECT HPV swab (SCS) and Evalyn Brush (EB), and one clinician-collected (CC) cervical specimen. Specimens were tested with the Alinity m HR HPV assay, and the results were used to determine positive and negative percent agreement (PPA and NPA), relative clinical sensitivity and specificity. RESULTS:For the combined populations (screening and referred to colposcopy), PPA and NPA between SCS and CC specimens were 94.0% and 86.0%, respectively, and between EB and CC specimens were 94.2% and 88.4%, respectively. The PPA and NPA between SCS and EB vaginal specimens were 95.5% and 93.7%. The relative clinical sensitivity for ≥ CIN2 between vaginal specimens and CC specimens was 1.00 and 1.02 for SCS and EB, respectively. The relative clinical specificity between vaginal specimens and CC specimens was 0.90 and 0.92 for SCS and EB specimens, respectively. CONCLUSION:This study is among the first US multicenter evaluations comparing 2 self-collection devices on the same molecular platform. It demonstrated that the clinical sensitivity of the Alinity m HR HPV assay for cervical disease detection (≥ CIN2) using both SCS and EB self-collected vaginal specimens is comparable to that in CC specimens. Overall, HPV agreement rates were consistent with those reported for other validated self-collected devices.
Cervical cancer screening in under-resourced areas presents significant challenges. Our project evaluated the integration of an HPV-based screening protocol in low resource clinics in Tijuana, Mexico. Our protocol featured point-of-care High Risk HPV (HR-HPV) screening through self- or provider collection, based on patient preference. HR-HPV positive patients were offered same or subsequent day colposcopy. Treatment was provided with thermal ablation. 62 patients were screened with 31% HR-HPV positivity rate. 60% preferred self-collection, and 40% preferred provider collection. Among test-positives, 53% underwent colposcopy, with a loss to follow up of 47%. 96% of respondents expressed willingness to recommend the program, Our conclusion is that HPV screening can be effectively implemented in low-resource clinics, with attention to logistical issues associated with new technology and specific social barriers.
OBJECTIVE:To identify barriers and facilitators to transitioning to primary human papillomavirus (HPV) testing from current cervical cancer screening practices among community OB/GYN physicians. METHODS:We conducted an exploratory qualitative study with in-depth interviews of 10 community-based OB/GYNs. Interviews were semistructured, utilizing an interview guide informed by the Consolidated Framework for Implementation Research, designed to explore current screening practices, perceptions of cytology versus primary HPV testing, recommended screening intervals, patient and physician acceptance of HPV-based testing, and anticipated changes in practice. Interviews were coded for recurring themes and organized into provider-, patient-, and system-level domains. RESULTS:Identified barriers included interprovider variability in cervical cancer screening practices, fear of missing a cancer, concerns about loss of follow-up, patient preferences for more frequent screening, and talking about HPV with patients as a stressful/difficult process. Identified facilitators included awareness of possible upcoming changes in cervical cancer screening recommendations and previous adjustments in approach to cervical cancer screening. CONCLUSIONS:Transitioning to this evidence-based cervical cancer screening modality will require targeted, multilevel strategies to address physician concerns and to promote the acceptability and adoption of primary HPV testing.
This study reports follow-up rates for abnormal Pap test results among inpatients screened through the Johns Hopkins Cervical Cancer Screening Program (CCSP). Between 2018 and 2023, 997 patients underwent screening in the CCSP. Of that total, 20.7% (206/997) had abnormal Pap tests warranting further care, and of these individuals, 54.5% did not follow-up. Individuals with a history of homelessness were significantly less likely to follow up (OR: 0.35). Those who had documented assistance for transportation were more likely to return for care (OR: 2.98), especially amongst individuals with a history of homelessness (OR: 4.84). The findings highlight potential targeted interventions based on housing and transportation assistance. Such interventions have been added to our inpatient protocol, with the goal of improving care continuity and effective screening.
OBJECTIVES:Persistent infection with high-risk human papillomavirus (HR-HPV) is a major cause of cervical precancerous lesions and cervical cancer. This study aimed to evaluate the effectiveness of Qingdu Suppository (QDS) in promoting HPV clearance and to identify predictors of treatment response. METHODS:This was a prospective observational cohort with retrospective analysis. A total of 60 patients with persistent HR-HPV infection were included (30 QDS and 30 non-QDS). The primary endpoint was HPV clearance, defined as 2 consecutive negative PCR results ≥6 months apart. Intention-to-treat (ITT, n=66, with lost-to-follow-up treated as persistent infection) and per-protocol (PP, n=60) analyses were performed. Inverse probability of treatment weighting (IPTW) was applied, and robust (sandwich) variance estimators were used to obtain valid confidence intervals. RESULTS:In the IPTW-weighted analysis, QDS was associated with higher HPV clearance than non-QDS (55.2% vs. 3.4%, p<.001). HPV clearance was significantly higher in the QDS group than in the non-QDS group (55.2% vs. 3.4%, p<.001). QDS remained an independent predictor of clearance (adjusted OR=33.1, 95% CI: 4.5-243.6, p=.001), with consistent benefits across subgroups. CONCLUSIONS:Using a strict endpoint of 2 consecutive negatives, QDS was associated with higher HPV clearance. Results were consistent across analytic approaches but should be interpreted with caution, given the limited sample size and nonrandomized design. QDS may represent a promising adjunctive therapy, but its efficacy and long-term benefits require confirmation in larger multicenter randomized controlled trials.
OBJECTIVE:This study aimed to investigate cellular composition and gene/pathway alterations in VLS tissue compared with normal skin using single-cell RNA sequencing (scRNA-seq) and lipid metabolomics. METHODS:scRNA-seq was conducted on 4 VLS samples and self-control vulvar skin. Lipid metabolism analysis was performed on 15 VLS samples. Bioinformatics assessed cellular abundance, differentially expressed genes (DEGs), and functional pathways between VLS and normal tissues. DEGs were validated via immunofluorescence. RESULTS:The authors found significant changes in cell-type abundance in the LS samples, with increased abundance of T cells, particularly the C01-GZMB/GZMK and C05-GNLY/XCL1 T cell subsets, and decreased abundance of fibroblasts, keratinocytes, and melanocytes. Furthermore, scRNA-seq data indicated distinct trends in the expression of key metabolic and inflammatory genes. Notably, lymphocyte-mediated immunity, leukocyte-mediated cytotoxicity, and cell-killing pathways were upregulated in the T cells of VLS, suggesting an ongoing inflammatory milieu. Cell communication analysis revealed an increase in the interactions among cell types, with the interaction intensity between T cells and fibroblasts showing the most pronounced increase. Immunofluorescence results revealed that GZMB and the pro-inflammatory factors, IFN-γ and TNF-β, were significantly increased in the VLS tissues. The epidermal keratin expression in the VLS tissue was abnormal, and the basal layer of the VLS tissue lost its normal single-layer structure, and the arrangement was disordered. CONCLUSION:Cellular composition changes in VLS T cells lead to apoptosis of normal skin cells, contributing to skin tissue destruction and playing a critical role in the inflammatory development of the disease.
