Applications of Machine Learning (ML) and Mathematical Modeling (MM) in Healthcare with Special Focus on Cancer Prognosis and Anticancer Therapy: Current Status and Challenges.

The use of data-driven high-throughput analytical techniques, which has given rise to computational oncology, is undisputed. The widespread use of machine learning (ML) and mathematical modeling (MM)-based techniques is widely acknowledged. These two approaches have fueled the advancement in cancer research and eventually led to the uptake of telemedicine in cancer care. For diagnostic, prognostic, and treatment purposes concerning different types of cancer research, vast databases of varied information with manifold dimensions are required, and indeed, all this information can only be managed by an automated system developed utilizing ML and MM. In addition, MM is being used to probe the relationship between the pharmacokinetics and pharmacodynamics (PK/PD interactions) of anti-cancer substances to improve cancer treatment, and also to refine the quality of existing treatment models by being incorporated at all steps of research and development related to cancer and in routine patient care. This review will serve as a consolidation of the advancement and benefits of ML and MM techniques with a special focus on the area of cancer prognosis and anticancer therapy, leading to the identification of challenges (data quantity, ethical consideration, and data privacy) which are yet to be fully addressed in current studies.

Reference standards for follicular density in ovarian cortex from birth to sexual maturity.

RESEARCH QUESTION: Are age-normalized reference values for human ovarian cortical follicular density adequate for tissue quality control in fertility preservation? DESIGN: Published quantitative data on the number of follicles in samples without known ovarian pathology were converted into cortical densities to create reference values. Next, a sample cohort of 126 girls (age 1-24 years, mean ± SD 11 ± 6) with cancer, severe haematological disease or Turner syndrome were used to calculate Z-scores for cortical follicular density based on the reference values. RESULTS: No difference was observed between Z-scores in samples from untreated patients (0.3 ± 3.5, n = 30) and patients treated with (0.5 ± 2.9, n = 48) and without (0.1 ± 1.3, n = 6) alkylating chemotherapy. Z-scores were not correlated with increasing cumulative exposure to cytostatics. Nevertheless, Z-scores in young treated patients (0-2 years -2.1 ± 3.1, n = 10, P = 0.04) were significantly lower than Z-scores in older treated patients (11-19 years, 2 ± 1.9, n = 15). Samples from patients with Turner syndrome differed significantly from samples from untreated patients (-5.2 ± 5.1, n = 24, P = 0.003), and a Z-score of -1.7 was identified as a cut-off showing good diagnostic value for identification of patients with Turner syndrome with reduced ovarian reserve. When this cut-off was applied to other patients, analysis showed that those with indications for reduced ovarian reserve (n = 15) were significantly younger (5.9 ± 4.2 versus 10.7 ± 5.9 years, P = 0.004) and, when untreated, more often had non-malignant haematologic diseases compared with those with normal ovarian reserve (n = 24, 100% versus 19%, P = 0.009). CONCLUSION: Z-scores allow the estimation of genetic- and treatment-related effects on follicular density in cortical tissue from young patients stored for fertility preservation. Understanding the quality of cryopreserved tissue facilitates its use during patient counselling. More research is needed regarding the cytostatic effects found in this study.

Endocrine disrupting chemicals interfere with decidualization of human primary endometrial stromal cells in vitro.

Multiple studies have shown associations between exposure to endocrine disrupting chemicals (EDCs) and reduced fertility in women. However, little is known about the target organs of chemical disruption of female fertility. Here, we focus on the hormone-sensitive uterine lining, the endometrium, as a potential target. Decidualization is the morphological and functional change that endometrial stromal cells undergo to support endometrial receptivity, which is crucial for successful implantation, placentation, and pregnancy. We investigated the effect of nine selected EDCs on primary human endometrial stromal cell decidualization in vitro. The cells were exposed to a decidualization-inducing mixture in the presence or absence of 1 µM of nine different EDCs for nine days. Extent of decidualization was assessed by measuring the activity of cAMP dependent protein kinase, Rho-associated coiled-coil containing protein kinase, and protein kinase B in lysates using photoluminescent probes, and secretion of prolactin into the media by using ELISA. Decidualization-inducing mixture upregulated activity of protein kinases and prolactin secretion in cells derived from all women. Of the tested chemicals, dichlorodiphenyldichloroethylene (p,p'-DDE), hexachlorobenzene (HCB) and perfluorooctanesulfonic acid (PFOS) significantly reduced decidualization as judged by the kinase markers and prolactin secretion. In addition, bisphenol A (BPA) reduced prolactin secretion but did not significantly affect activity of the kinases. None of the EDCs was cytotoxic, based on the assessment of total protein content or activity of the viability marker casein kinase 2 in lysates. These results indicate that EDCs commonly present in the blood circulation of reproductive-aged women can reduce decidualization of human endometrial stromal cells in vitro. Future studies should focus on detailed hazard assessment to define possible risks of EDC exposure to endometrial dysfunction and implantation failure in women.

Potential of Microneedle Systems for COVID-19 Vaccination: Current Trends and Challenges.

To prevent the coronavirus disease 2019 (COVID-19) pandemic and aid restoration to prepandemic normality, global mass vaccination is urgently needed. Inducing herd immunity through mass vaccination has proven to be a highly effective strategy for preventing the spread of many infectious diseases, which protects the most vulnerable population groups that are unable to develop immunity, such as people with immunodeficiencies or weakened immune systems due to underlying medical or debilitating conditions. In achieving global outreach, the maintenance of the vaccine potency, transportation, and needle waste generation become major issues. Moreover, needle phobia and vaccine hesitancy act as hurdles to successful mass vaccination. The use of dissolvable microneedles for COVID-19 vaccination could act as a major paradigm shift in attaining the desired goal to vaccinate billions in the shortest time possible. In addressing these points, we discuss the potential of the use of dissolvable microneedles for COVID-19 vaccination based on the current literature.

Persistent organic pollutants and the size of ovarian reserve in reproductive-aged women.

Industrial chemicals such as persistent organic pollutants (POPs) have been associated with reduced fertility in women, including longer time-to-pregnancy (TTP), higher odds for infertility, and earlier reproductive senescence. Fertility is highly dependent on the ovarian reserve, which is composed of a prenatally determined stock of non-growing follicles. The quantity and quality of the follicles decline with age, thereby eventually leading to menopause. In the clinical setting, assessing ovarian reserve directly through the histological analysis of follicular density in ovaries is not practical. Therefore, surrogate markers of ovarian reserve, such as serum anti-Müllerian hormone (AMH) are typically used. Here, we studied associations between chemical exposure and ovarian reserve in a cohort of pregnant women undergoing elective caesarean section (n = 145) in Stockholm, Sweden. Full data (histological, clinical, serum) were available for 50 women. We estimated the size of the reserve both directly by determining the density of follicles in ovarian cortical tissue samples, and indirectly by measuring AMH in associated serum samples. Concentrations of 9 organochlorine pesticides (OCPs), 10 polychlorinated biphenyls (PCBs), 3 polybrominated diphenylethers (PBDEs) and 9 perfluoroalkyl substances (PFAS) were determined in serum, and clinical data were retrieved from electronic medical records. Healthy follicle densities (median 0, range 0-193 follicles/mm3) and AMH levels (median 2.33 ng/mL, range 0.1-14.8 ng/mL) varied substantially. AMH correlated with the density of growing follicles. Twenty-three chemicals detected in more than half of the samples were included in the analyses. None of the chemicals, alone or as a mixture, correlated with AMH, growing or atretic follicles. However, HCB, transnonachlor, PCBs 74 and 99 were associated with decreased non-growing follicle densities. HCB and transnonachlor were also negatively associated with healthy follicle density. Further, mixture of lipophilic POPs (PBDE 99, p,p'-DDE, and PCB 187) was associated with lower non-growing follicle densities. In addition, exposure to HCB, p,p'-DDE, and mixture of OCPs were significantly associated with higher odds of infertility. The results suggest that exposure to chemicals may reduce the size of ovarian reserve in humans, and strongly encourage to study mechanisms behind POP-associated infertility in women in more detail.

Fertility Preservation for Prepubertal Patients at Risk of Infertility: Present Status and Future Perspectives.

The increasing cure rate of cancer has led to a vast population of survivors having to face the late adverse effects of oncological treatments, with fertility impairment being one of the most sensitive issues for patients. Different options to preserve the fertility of adult patients are routinely used in clinical practice. However, fertility preservation strategies for prepubertal patients at risk of infertility are limited to the cryopreservation of immature gonadal tissue. In recent decades, many research efforts have been focused on the future use of cryopreserved gonadal tissue. This review discusses the common status of fertility preservation measures for pediatric patients undergoing gonadotoxic treatment, focusing especially on the challenges that remain to be solved in order to implement this fundamental service.

Hypercholesterolemia impairs megakaryopoiesis and platelet production in scavenger receptor BI knockout mice.

BACKGROUND AND AIMS: Thrombocytopenia in scavenger receptor BI (SR-BI) knockout mice is suggested to result from augmented platelet clearance induced by elevated intracellular unesterified cholesterol (UC) levels. We hypothesize that SR-BI deficiency may also influence platelet production at the level of its precursor cell in the bone marrow, the megakaryocyte. METHODS: In this study, we compared megakaryopoiesis and platelet production in SR-BI knockout and wild-type mice. RESULTS: In line with our hypothesis, megakaryocytes from SR-BI knockout mice exhibited UC accumulation while no accumulation of UC was detectable in wild-type megakaryocytes. Bone marrow expression of transcription factors involved in megakaryocyte maturation was induced, but megakaryocyte counts were unchanged in bone marrow of SR-BI knockout mice. Interestingly, we did find a striking 62% decrease (p < 0.01) in proplatelet production by SR-BI knockout megakaryocytes. SR-BI knockout mice displayed an impaired increase in circulating platelet concentrations and bone marrow megakaryocyte numbers upon thrombopoietin challenge. Importantly, megakaryocytes from normolipidemic bone marrow-specific SR-BI knockout mice exhibited a normal ability to produce proplatelets. Moreover, bone marrow-specific deletion of SR-BI did not impair the thrombopoietin response or induce thrombocytopenia, confirming that absence of megakaryocyte SR-BI does not underlie the thrombocytopenic phenotype in total body SR-BI knockout mice. CONCLUSIONS: In conclusion, the elevation of plasma unesterified cholesterol levels impairs megakaryopoiesis and platelet production in SR-BI knockout mice. Our findings suggest that, in addition to an increased platelet clearance, a decrease in platelet production may also, in part, explain the thrombocytopenic phenotype associated with SR-BI deficiency in mice.

Predilection of Low Protein C-induced Spontaneous Atherothrombosis for the Right Coronary Sinus in Apolipoprotein E deficient mice.

Silencing of anticoagulant protein C using RNA interference (siProc) evokes low incident but spontaneous atherothrombosis in the aortic root of apolipoprotein E-deficient (Apoe-/-) mice. The aims of the current study were (1) to analyze if plaque characteristics or circulating factors could be linked to atherothrombosis susceptibility, (2) to increase the incidence of atherothrombosis by transiently increasing blood pressure, and (3) to direct atherothrombosis to an additional predefined vascular site by applying a semi-constrictive collar around the carotid artery. siProc-driven spontaneous atherothrombosis in the aortic root of Apoe-/- mice was reproduced and occurred at an incidence of 23% (9 out of 39 mice), while the incidence of collar-induced atherothrombosis in the carotid artery was 2.6% (1 out of 39 mice). Treatment with phenylephrine, to transiently increase blood pressure, did not increase atherothrombosis in the aortic root of the Apoe-/- mice nor in the carotid arteries with collars. Plaques in the aortic root with an associated thrombus were lower in collagen and macrophage content, and mice with atherothrombosis had significantly more circulating platelets. Plasma protein C, white blood cell counts, total cholesterol, fibrinogen, serum amyloid A, and IL-6 were not different amongst siProc treated mice with or without thrombosis. Remarkably, our data revealed that thrombus formation preferably occurred on plaques in the right coronary sinus of the aortic root. In conclusion, there is a predilection of low protein C-induced spontaneous atherothrombosis in Apoe-/- mice for the right coronary sinus, a process that is associated with an increase in platelets and plaques lower in collagen and macrophage content.

Long-Term Changes in Backscattered Light Measurements in Keratoconus Corneas Treated with Collagen Cross-Linking.

PURPOSE: Our aim was to compare densitometry data between keratoconus and normal corneas and to assess the long-term changes in corneal backscattered light values after corneal collagen cross-linking (CXL) treatment. MATERIAL AND METHODS: Retrospective analysis was performed on 26 eyes of normal patients (age: 32.71 ± 12.68 years) and 39 eyes of keratoconus patients (28.93 ± 7.59 years) using the Pentacam HR corneal densitometry module before CXL and during the postoperative period, which lasted a mean of 2.53 years (range: 1-4 years). Corneal backscattered light values in grey scale unit (GSU) were recorded for the anterior 120 µm, the center layer, and the posterior 60 µm of the cornea in four concentric, central rings. An additional calculation was performed with converting GSU values to GSU/cubic millimeters (mm3) with surface area calculations and using corneal thickness data. RESULTS: Statistically significant differences were observed between normal and keratoconus group densitometry values (in GSU/mm3) in all annuli of the center layer; all, but anterior layer of the 10-12 annuli; all annuli of the total thickness and in all values of the total diameter. In all these cases, the normal cornea showed higher GSU/mm3 values compared to keratoconus corneas (p < 0.05). One month after the CXL treatment, the GSU/mm3 data increased significantly in the anterior, the center, and the posterior zone (p < 0.05), followed by its slow decrease. At the end of the follow-up period, the GSU/mm3 values were significantly higher in all three zones compared to those before the CXL treatment (p < 0.01). CONCLUSION: Densitometry measurements can reflect the changes of optical quality of the cornea. These measurements may play a valuable role in assessing keratoconus and optical changes of the corneas after CXL treatment.

Uterine disorders in 50 pet rabbits.

Although the incidence of uterine disorders in pet rabbits is high there are only a few retrospective studies and case reports on genital tract disease in female rabbits. Uterine disorders were assessed in 50 pet rabbits. In 31 pet rabbits with suspected clinical uterine disease, medical records were further reviewed regarding clinical signs, diagnostic workup, treatment as well as the outcome itself. Uterine adenocarcinoma (54%) was most frequently diagnosed, followed by endometrial hyperplasia (26%). Serosanguineous vaginal discharge was the predominant clinical sign observed by the rabbit owners. In approximately 50% of the rabbits with suspected uterine disorders, abdominal palpation revealed enlarged and/or irregular masses in the caudoventral abdomen indicating uterine lesions. Out of 23 rabbits undergoing ovariohysterectomy, four were either euthanized or died shortly after surgery because they were clinically unstable. Overall, 80% of the ovariohysterectomized animals were still alive 6 mo after surgery. In female pet rabbits that are not breeding, either ovariohysterectomy should be performed at an early age or routine checks including ultrasonography of the abdomen are recommended on a regular basis.

Thymomas in rabbits: clinical evaluation, diagnosis, and treatment.

Thymomas are rarely recorded in rabbits, and the literature includes comparatively few cases. Medical records were reviewed to identify all pet rabbits in which a mediastinal mass was diagnosed between Feb 2007 and Jan 2010. Signalment, history, clinical signs, diagnostic work-up (including laboratory data, diagnostic imaging, and ultrasound-guided fine-needle aspiration of the mediastinal mass), treatment modalities, survival time, and histologic findings were evaluated. Cytologic and/or histopathologic examinations revealed thymomas in all rabbits with mediastinal masses (n=13). Rabbits with thymomas showed clinical signs of dyspnea (76.9%), exercise intolerance (53.9%), and bilateral exophthalmos (46.2%). In seven rabbits the thymoma was removed surgically. Two rabbits were treated conservatively, and four rabbits were euthanized because of their poor clinical condition. The two rabbits that underwent surgery were euthanized 6 mo and 34 mo later. Mediastinal masses in rabbits appear to be more common than previously believed and consist primarily of thymomas rather than thymic lymphomas. Cytology of samples collected by ultrasound-guided fine-needle aspiration is an accurate diagnostic tool for the identification of thymomas in rabbits. Due to a high rate of perioperative mortality, intensive perioperative care and the provision of a low-stress environment are recommended for a successful thoracotomy.

Clinical symptoms and diagnosis of encephalitozoonosis in pet rabbits.

Infections with Encephalitozoon cuniculi in rabbits are observed at increasing frequency and are known as opportunistic infections in immunocompromised humans. 191 pet rabbits with suspected encephalitozoonosis, presented at the Animal Hospital of the Veterinary University of Vienna (Austria), were included in this study. Rabbits were serologically examined for antibodies against E. cuniculi (144 positive out of 184 rabbits with suspected encephalitozoonosis compared to 14 positive out of 40 clinically healthy rabbits tested as part of a standard health check) and Toxoplasma gondii (8 positive out of 157). Of the 144 seropositive rabbits with clinical signs, 75% showed neurological symptoms, 14.6% demonstrated phacoclastic uveitis and 3.5% suffered from renal failure. 6.9% of the animals had combined symptoms. Vestibular disease dominated within the rabbits that showed neurological symptoms. Polymerase chain reaction (PCR) could not detect parasite DNA in urine or cerebrospinal fluid (CSF), but did so in 4 out of 5 samples of liquefied lens material in cases with phacoclastic uveitis due to lens capsule rupture. Additionally further diagnostic procedures, such as inspection of the external ear canal (N=69), radiography of the tympanic bullae (N=65) were performed to rule out differential diagnosis. 54.2% of the patients exhibiting neurological symptoms recovered within a few days, while 87.5% of the rabbits suffering from renal failure died or had to be euthanized.

Malignant B-cell lymphoma of the Harder's gland in a rabbit.

A 22-month-old, female rabbit was presented with a 1-day history of acute unilateral exophthalmos. Ultrasonography and computed tomography (CT) of the orbit revealed an orbital mass. Retrobulbar lymphoma was diagnosed following fine-needle aspiration biopsy (FNAB). Thoracic radiographs were normal, and ultrasonography of the abdomen showed focal hypoechoic thickening of the bowel wall and hypoechoic enlarged lymph nodes. The rabbit was euthanized and histopathology identified the retrobulbar mass as B-cell malignant lymphoma of the Harder's gland. Mesenteric lymph nodes, caecum, and both kidneys were also affected. This is the first documented case of malignant lymphoma of the Harder's gland in a rabbit.