Treatment and Management of Loin Pain Hematuria Syndrome.

PURPOSE OF REVIEW: Loin pain hematuria syndrome (LPHS) is rare and seldom diagnosed, yet it has a particularly significant impact on those affected. This is a review of the latest and seminal evidence of the pathophysiology and diagnosis of LPHS and presents the typical clinical presentation and treatment options available. RECENT FINDINGS: LPHS is typically found in young women with characteristic symptoms, including severe recurrent flank pain and gross or microscopic hematuria. The majority of patients will experience crippling pain for many years without effective therapy, often requiring frequent use of narcotic medication. However, the lack of conclusive pathophysiology, in conjunction with the rarity of LPHS, has prohibited the development and trial of definitive treatment options. Nevertheless, in order to combat this rare but severe disease, management strategies have continued to evolve, ranging from conservative measures to invasive procedures. This review presents an overview of the current hypotheses on the pathophysiology of LPHS in addition to summarizing the management strategies that have been utilized. Only 30% of LPHS patients will experience spontaneous resolution, whereas the majority will continue to face chronic, crippling pain. Several methods of treatment, including invasive and non-invasive, may provide an improved outcome to these patients. Treatment should be individually tailored and multi-disciplinary in nature. Further research is required to further elucidate the pathophysiology and develop new, specific, treatment options.

Phase II trial of bevacizumab and sorafenib in recurrent ovarian cancer patients with or without prior-bevacizumab treatment.

OBJECTIVE: To examine whether blocking multiple points of the angiogenesis pathway by addition of sorafenib, a multi-kinase inhibitor against VEGFR2/3, Raf, c-Kit, and PDGFR, to bevacizumab would yield clinical activity in ovarian cancer (OvCa). METHODS: This phase II study tested bevacizumab plus sorafenib in two cohorts; bevacizumab-naïve and bevacizumab-exposed patients. Bevacizumab (5 mg/kg IV every 2 weeks) was given with sorafenib 200 mg bid 5 days-on/2 days-off. The primary objective was response rate using a Simon two-stage optimal design. Progression-free survival (PFS) and toxicity were the secondary endpoints. Exploratory correlative studies included plasma cytokine concentrations, tissue proteomics and dynamic contrast-enhanced-magnetic resonance imaging (DCE-MRI). RESULTS: Between March 2007 and August 2012, 54 women were enrolled, 41 bevacizumab-naive and 13 bevacizumab-prior, with median 5 (2-9) and 6 (5-9) prior systemic therapies, respectively. Nine of 35 (26%) evaluable bevacizumab-naive patients attained partial responses (PR), and 18 had stable disease (SD) ≥ 4 months. No responses were seen in the bevacizumab-prior group and 7 (54%) patients had SD ≥ 4 months, including one exceptional responder with SD of 27 months. The overall median PFS was 5.5 months (95%CI: 4.0-6.8 months). Treatment-related grade 3/4 adverse events (≥5%) included hypertension (17/54 [31%]; grade 3 in 16 patients and grade 4 in one patient) and venous thrombosis or pulmonary embolism (5/54 [9%]; grade 3 in 4 patients and grade 4 in one patient). Pretreatment low IL8 concentration was associated with PFS ≥ 4 months (p = .031). CONCLUSIONS: The bevacizumab and sorafenib combination did not meet the pre-specified primary endpoint although some clinical activity was seen in heavily-pretreated bevacizumab-naive OvCa patients with platinum-resistant disease. Anticipated class toxicities required close monitoring and dose modifications.

A Comprehensive Review of the Treatment and Management of Myofascial Pain Syndrome.

PURPOSE OF REVIEW: Myofascial pain syndrome (MPS) is a musculoskeletal pain condition that stems from localized, taut regions of skeletal muscle and fascia, termed trigger points. The purpose of this comprehensive review is to provide updated information on prevalence, pathophysiology, and treatment modalities with a focus on interventional modalities in managing MPS. RECENT FINDINGS: Though MPS can present acutely, it frequently presents as a chronic condition, affecting up to 85% of adults during their lifetime. MPS is an often-overlooked component of pain with overarching effects on society, including patient quality of life, physical and social functioning, emotional well-being, energy, and costs on health care. The prevalence of MPS is generally increased among patients with other chronic pain disorders and has been associated with various other conditions such as bladder pain syndrome, endometriosis, and anxiety. MPS is poorly understood and remains a challenging condition to treat. Non-pharmacologic treatment modalities such as acupuncture, massage, transcutaneous electrical stimulation, and interferential current therapy may offer relief to some patients with MPS. Additional studies are warranted to get a better understanding of managing myofascial pain.

Defective entry into mitosis 1 (Dim1) negatively regulates osteoclastogenesis by inhibiting the expression of nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 1 (NFATc1).

Bone remodeling is a continuous process of osteoblastic bone formation and osteoclastic bone resorption to maintain normal bone mass. NFATc1 is the master regulator of osteoclastogensis and transcriptionally activated by c-Fos and NF-κB in response to receptor activator of NF-κB ligand (RANKL) treatment. Defective entry into mitosis 1 (Dim1) is a nuclear protein that is implicated in pre-mRNA splicing and cell cycle progression, but the possible role of Dim1 in regulating other cellular processes remains unknown. Here, we demonstrate that Dim1 attenuates RANKL-induced osteoclastogenesis by targeting NFATc1 signaling pathway. Expression levels of Dim1 and NFATc1 are significantly increased during the formation of multinucleated osteoclasts. RNAi-mediated knockdown of Dim1 markedly enhances the expression of NFATc1 and its target genes, leading to the increase of RANKL-induced osteoclastogenesis in bone marrow-derived macrophages. Conversely, ectopic expression of Dim1 decreases RANKL-induced osteoclast differentiation by silencing NFATc1 and its target genes, further linking Dim1 to the dynamic regulation of osteoclastogenesis. Consistent with this notion, ChIP and interaction studies show that Dim1 directly associates with c-Fos and prevents c-Fos from binding to the NFATc1 promoter, resulting in targeted inactivation of the NFATc1 gene. Therefore, our studies reveal an unrecognized role for Dim1 as a master modulator of osteoclast differentiation, as well as the molecular mechanism underlying its repressive action toward osteoclastogensis.

Pediatric Trauma Recidivism: A Statewide Risk Factor Analysis of the Maryland Health Services Cost Review Commission (HSCRC).

BACKGROUND: National estimates suggest pediatric trauma recidivism is uncommon but are limited by short follow up and narrow ascertainment. We aimed to quantify the long-term frequency of trauma recidivism in a statewide pediatric population and identify risk factors for re-injury. METHODS: The Maryland Health Services Cost Review Commission Dataset was queried for 0-19-year-old patients with emergency department or inpatient encounters for traumatic injuries between 2013 and 2019. We measured trauma recidivism by identifying patients with any subsequent presentation for a new traumatic injury. Univariate and multivariable regressions were used to estimate associations of patient and injury characteristics with any recidivism and inpatient recidivism. RESULTS: Of 574,472 patients with at least one injury encounter, 29.6% experienced trauma recidivism. Age ≤2 years, public insurance, and self-inflicted injuries were associated with recidivism regardless of index treatment setting. Of those with index emergency department presentations 0.06% represented with an injury requiring inpatient admission; unique risk factors for ED-to-inpatient recidivism were age >10 years (aOR 1.61), cyclist (aOR 1.31) or burn (aOR 1.39) mechanisms, child abuse (aOR 1.27), and assault (aOR 1.43). Among patients with at least one inpatient encounter, 6.3% experienced another inpatient trauma admission, 3.4% of which were fatal. Unique risk factors for inpatient-to-inpatient recidivism were firearm (aOR 2.48) and motor vehicle/transportation (aOR 1.62) mechanisms of injury (all p < 0.05). CONCLUSIONS: Pediatric trauma recidivism is more common and morbid than previously estimated, and risk factors for repeat injury differ by treatment setting. Demographic and injury characteristics may help develop and target setting-specific interventions. LEVEL OF EVIDENCE: III (Retrospective Comparative Study).

The UTHealth Houston Adult Cardiovascular Genomics Certificate Program: Efficacy and Impact on Healthcare Professionals.

Background: The demand for genetic services has outpaced the availability of resources, challenging clinicians untrained in genetic integration into clinical decision-making. The UTHealth Adult Cardiovascular Genomics Certificate (CGC) program trains non-genetic healthcare professionals to recognize, assess, and refer patients with heritable cardiovascular diseases. This asynchronous online course includes 24 modules in three tiers of increasing complexity, using realistic clinical scenarios, interactive dialogues, quizzes, and tests to reinforce learning. We hypothesized that the CGC will increase genomic competencies in this underserved audience and encourage applying genomic concepts in clinical practice. Methods: Required course evaluations include pre- and post-assessments, knowledge checks in each module, and surveys for module-specific feedback. After 6 months, longitudinal feedback surveys gathered data on the long-term impact of the course on clinical practice and conducted focused interviews with learners. Results: The CGC was accredited in September 2022. Principal learners were nurses (24%), nurse practitioners (21%), physicians (16%), and physician assistants. Scores of 283 learners in paired pre- and post-assessments increased specific skills related to recognizing heritable diseases, understanding inheritance patterns, and interpreting genetic tests. Interviews highlighted the CGC's modular structure and linked resources as key strengths. Learners endorsed confidence to use genetic information in clinical practice, such as discussing genetic concepts and risks with patients and referring patients for genetic testing. Learners were highly likely to recommend the CGC to colleagues, citing its role in enhancing heritable disease awareness. Conclusions: The CGC program effectively empowers non-genetic clinicians to master genomic competencies, fostering collaboration to prevent deaths from heritable cardiovascular diseases, and potentially transforming healthcare education and clinical practice.

BLM overexpression as a predictive biomarker for CHK1 inhibitor response in PARP inhibitor-resistant BRCA-mutant ovarian cancer.

Poly(ADP-ribose) polymerase inhibitors (PARPis) have changed the treatment paradigm in breast cancer gene (BRCA)-mutant high-grade serous ovarian carcinoma (HGSC). However, most patients eventually develop resistance to PARPis, highlighting an unmet need for improved therapeutic strategies. Using high-throughput drug screens, we identified ataxia telangiectasia and rad3-related protein/checkpoint kinase 1 (CHK1) pathway inhibitors as cytotoxic and further validated the activity of the CHK1 inhibitor (CHK1i) prexasertib in PARPi-sensitive and -resistant BRCA-mutant HGSC cells and xenograft mouse models. CHK1i monotherapy induced DNA damage, apoptosis, and tumor size reduction. We then conducted a phase 2 study (NCT02203513) of prexasertib in patients with BRCA-mutant HGSC. The treatment was well tolerated but yielded an objective response rate of 6% (1 of 17; one partial response) in patients with previous PARPi treatment. Exploratory biomarker analyses revealed that replication stress and fork stabilization were associated with clinical benefit to CHK1i. In particular, overexpression of Bloom syndrome RecQ helicase (BLM) and cyclin E1 (CCNE1) overexpression or copy number gain/amplification were seen in patients who derived durable benefit from CHK1i. BRCA reversion mutation in previously PARPi-treated BRCA-mutant patients was not associated with resistance to CHK1i. Our findings suggest that replication fork-related genes should be further evaluated as biomarkers for CHK1i sensitivity in patients with BRCA-mutant HGSC.

Treatment and Management of Xiphoidalgia.

Xiphodynia is a rare but debilitating condition that can be described as a form of pain on the xiphisternal joint or any related structures that are anchored to the xiphoid process. Although xiphodynia is a musculoskeletal pain in nature, the pain located in the anterior chest can commonly mislead physicians into pursuing other diagnoses such as cardiac diseases. This leads to a prolonged duration of pain before receiving treatment. In the attempt to alleviate pain resulting from this condition, physicians have previously utilized a range of treatment options, including conservative management, injections, or in severe cases, xiphoidectomy. In this review, we aim to give a brief overview of xiphodynia, including clinical diagnoses and current treatment modalities. Key Summary Points: 1. Xiphodynia can be described as pain radiating from an irritated xiphoid process that can travel to the chest, abdomen, throat, and arms2. Risk factors for developing secondary xiphoidalgia include GERD, gall-bladder disease, angina pectoris, and coronary-artery disease3. The treatment of xiphodynia can range from conservative management to injections or a xiphoidectomy4. Further research is required to develop a standardized treatment protocol and currently the choice of treatment depends on the patient's individual case and the degree of severity.

Association of Parental Factors and Insulin-like Growth Factor 2 Polymorphism with Intrauterine Growth Restriction.

Polymorphism of insulin-like growth factor 2 (IGF2) is known to play a role in cell development. Only the paternal IGF2 copy is active, while the copy inherited from the mother is inactive. This study aimed to explore whether maternal and paternal factors influence IGF2 polymorphism in newborns with intrauterine growth restriction (IUGR) compared to appropriate for gestational age (AGA). A cross-sectional exploratory study was conducted from June 2014 to November 2015 at the Neonatology, Gynecology 1 Clinic, Cluj-Napoca, Romania. The ApaI IGF2 genotypes and allele frequencies were similar in the IUGR and AGA groups (p-value > 0.10). The IUGR babies with a protective IGF2 genetic profile had significantly younger parents (a difference in the median age of 8 years for mothers and 9 years for fathers; p-value < 0.009). The IUGR babies had parents with lower birth weights than AGA babies (mothers' medians: 2800 g vs. 3100 g; fathers' medians: 3000 g vs. 3400 g; p-value < 0.02). In univariable regression analysis, the mother's and father's birth weight proved to be associated with IUGR. The father's birth weight proved to be the only factor significantly associated with IUGR, independent of the mother's birth weight or the presence of a protective IGF2 genetic profile (odd ratio = 0.998 [0.996 to 1.000], p-value = 0.032).

Krukenberg tumor in pregnancy: a rare case and review of the literature.

Krukenberg's tumor diagnosed in pregnancy is an uncommon situation that raises both diagnosis and medical management issues. We performed a review of the existing literature regarding this pathology, diagnostic means and therapeutic approaches, motivated by a case in our own practice. A 35-year-old primigravida was diagnosed with an adnexal mass during the first trimester prenatal ultrasound. Ultrasound revealed a 10 cm right adnexal mass with multiple septae, richly vascularized, whose presence and characteristics were confirmed by magnetic resonance imaging. Due to the progressively increasing tumor size, laparoscopy was performed with right adnexectomy and peritoneal biopsies. Histopathology diagnosed a metastatic ovarian tumor from a mucinous colorectal adenocarcinoma. After delivery the patient was further investigated and diagnosed with sigmoid cancer. Even though ovarian cancer in pregnancy is rare, adnexal ultrasound is mandatory when scanning during the first trimester to rule out the presence of associated fallopian or ovarian masses.

Recent advancements of antiangiogenic combination therapies in ovarian cancer.

Ovarian cancer is a deadly malignancy with a growing therapeutic armamentarium, though achieving sustained benefit in the clinic remains largely elusive. Through biomarker and genetic analysis, several pathways of resistance and sensitivity to commonly used therapeutics have been identified, expanding the potential of identifying unique drug combinations and indicating new directions for improving clinical outcomes. Here, we review the mechanisms of angiogenic response and antiangiogenic therapy in ovarian cancer, as well as the interactions it exhibits with the immune and DNA damage response pathways. We discuss results from clinical trials examining the combinations of antiangiogenics, PARP inhibitors, and immune checkpoint inhibitors are also discussed, as well as several ongoing trials.

Topical Sevoflurane: A Novel Treatment for Chronic Pain Caused by Venous Stasis Ulcers.

In the US, an estimated 1 - 2% of chronic venous insufficiency (CVI) patients (of 6 - 7 million nationwide) develop at least one venous stasis ulcer (VSU) during their illness. Of these, approximately 40% develop subsequent ulcers, making VSU prognostically poor. Current management of VSU is costly, with poor prognosis, high recurrence rate, inadequate pain management, and significantly reduced quality of life (QoL). Topical volatile anesthetic agents, such as sevoflurane, offer improved pain relief and symptom control in patients suffering from chronic VSU. The immediate impact of topical sevoflurane in reducing pain associated with ulcer bed debridement has several implications in improving the quality of life in patients with CVI induced ulcers and in the prognosis and healing of the ulcers. This review summarizes a topical formulation of a volatile anesthetic and its implications for the management of VSUs.

Basivertebral Nerve Ablation for the Treatment of Vertebrogenic Pain.

Chronic low back pain affects a significant portion of patients worldwide and is a major contributor to patient disability; however, it is a difficult problem to diagnose and treat. The prevailing model of chronic low back pain has presumed to follow a discogenic model, but recent studies have shown a vertebrogenic model that involves the basivertebral nerve (BVN). Radiofrequency ablation of the BVN has emerged as a possible nonsurgical therapy for vertebrogenic low back pain. The objective of this manuscript is to provide a comprehensive review of vertebrogenic pain diagnosis and our current understanding of BVN ablation as treatment.

Correction: Self-reported and clinical periodontal conditions in a group of Eastern European postpartum women.

[This corrects the article DOI: 10.1371/journal.pone.0237510.].

Assessing the diagnostic accuracy for pleomorphic adenoma and Warthin tumor by employing the Milan System for Reporting Salivary Gland Cytopathology: An international, multi-institutional study.

BACKGROUND: The Milan System for Reporting Salivary Gland Cytopathology (MSRSGC) has established distinct diagnostic categories for reporting cytopathological findings, and each is associated with a defined risk of malignancy (ROM). However, the ROM is applied at the overall category level and is not specific for particular morphological entities within a category. Here, the diagnostic performance of the MSRSGC for pleomorphic adenoma (PA) and Warthin tumor (WT) is reported. METHODS: The pathology archives of 11 institutions from 4 countries were retrospectively searched to identify all salivary gland fine-needle aspiration (FNA) biopsies with a differential or definitive diagnosis of PA or WT and all resection specimens with a diagnosis of PA or WT; only paired cases were included. All FNA diagnoses were retrospectively classified according to the MSRSGC. RESULTS: A total of 1250 cases met the inclusion criteria, and they included 898 PA cases and 352 WT cases. The ROM in the benign neoplasm category was 3.0% and 1.3% for cases with a differential or definitive diagnosis of PA and WT, respectively. The ROM in the salivary gland neoplasm with uncertain malignant potential (SUMP) category was 2.7% and 18.8% for PA and WT, respectively (P = .0277). The diagnostic accuracy for PA and WT was 95.1% and 96.1%, respectively. CONCLUSIONS: The diagnostic accuracy for PA and WT on FNA is high. Furthermore, these findings highlight the difference in the ROMs associated with 2 specific differential diagnoses in the SUMP category: basaloid neoplasms and oncocytoid neoplasms.

Adenoid cystic carcinoma cytology: Salivary gland and nonsalivary gland.

OBJECTIVES: Adenoid cystic carcinoma (ACCA) is an uncommon primary malignancy of salivary glands and rarely nonsalivary tissue. This study aims to evaluate the diagnostic accuracy of ACCA on fine needle aspiration (FNA) material and the associated challenges. METHODS: A search on electronic pathology database from 2006 to 2016 at The Johns Hopkins Hospital found 83 cytology specimens diagnosed as ACCA, 49 with histology follow-up. RESULTS: Fifty-two females and 31 males were found ranging from 37 to 95 years old (mean 62.5). The tumor size was 1 to 11.5 cm (mean 3.4). FNAs were performed on 46 salivary glands (54.88%), 12 head and neck masses (14.45%), 9 lymph nodes (10.84%), 9 tracheas/lungs (10.84%), 4 vaginal/perineum/gluteal masses (4.82%), and one for each kidney, liver and abdominal/pelvic mass (1.21%). 83 FNA diagnoses revealed 3 nondiagnostics (3.61%), 20 neoplasms with unspecified features (24.10%), 30 basaloid neoplasms (36.14%), 18 ACCA (21.69%), and 12 other malignancies (14.46%). The accuracy of FNA in diagnosis of ACCA comparing to histologic follow-up in 49 cases was 87.5% sensitivity, 66.67% specificity, with 92.11% positive predictive value and 54.55% negative predictive value. The most common mimicker was pleomorphic adenoma. CONCLUSION: ACCA can be diagnosed not only in the salivary gland FNAs, but also respiratory tract, intra-abdominal, kidney, and gynecologic regions. FNA is a preferred technique to assess mass lesions. However, a diagnosis of ACCA on FNA material should be rendered with caution since there are benign and malignant neoplasms with overlapping features. Awareness of prior medical history and ancillary studies can improve the diagnosis.

Utilization of B12 for the treatment of chronic migraine.

Chronic migraine is a particular classification of a headache that is typically unilateral and pulsatile and lasts for at least 3 months. Owing to its high prevalence and detrimental impact on personal, social, and economic aspects of patient lives, much desire has gone into fully understanding the pathogenesis of migraine, and to search for therapeutic agents. In addition to current therapeutics such as triptans, ergotamine, and monoclonal antibodies targeting calcitonin gene-related peptide receptors, vitamin B12 has been investigated for its possible use as a prophylactic agent for migraines. Specifically, the observed effects of vitamin B12 on nitric oxide and homocysteine prompt further investigation of its underlying mechanisms in migraine pathophysiology. In this comprehensive review, we provide a brief overview of migraines and current therapies while focusing on the promising role of vitamin B12 as a possible treatment option for chronic migraine management.

lncRNA 5430416N02Rik Promotes the Proliferation of Mouse Embryonic Stem Cells by Activating Mid1 Expression through 3D Chromatin Architecture.

Both 3D chromatin architecture and long non-coding RNAs (lncRNAs) play essential roles in pluripotency maintenance. However, whether lncRNAs are involved in organizing 3D chromatin structure remains largely unexplored. We identified 39 lncRNAs bound by Klf4, among which we further revealed the 5430416N02Rik promoter is a chromatin interaction hub. Knockout of the 5430416N02Rik locus reduces the proliferation rate of embryonic stem cells (ESCs). Moreover, deleting both the promoter and the gene body of 5430416N02Rik causes a more severe proliferation defect and has a more profound impact on the transcriptome than deleting the gene body alone. The reduced proliferation of the 5430416N02Rik locus knockout ESCs is mainly due to the downregulation of Mid1, the expression of which requires the inter-chromosomal interaction between Mid1 and 5430416N02Rik loci. In summary, our data demonstrated that the lncRNA 5430416N02Rik gene locus maintains the fast proliferation of ESCs by activating the expression of Mid1 through chromatin interaction.

Treatment recommendations for chronic knee osteoarthritis.

Primary osteoarthritis (OA) hinders an aging global population as one of the leading causes of years-lost-to-disability (YLD). OA in most patients is considered to be an overuse injury that results in degenerative inflammation of the joints with the associated formation of bony outgrowths. Due to the escalating nature of this chronic pain disease, treatment management for OA can initially begin with a more conservative approach. It can eventually lead to more invasive surgical procedures. At present, the standard of care remains initial conservative management with lifestyle changes, including weight loss with concurrent anti-inflammatory regimens. Injections are frequently used for the escalation of care, but a significant number of patients ultimately resort to total knee arthroplasty. This review will focus specifically on knee OA, providing a brief overview of risk factors and early management and in-depth exploration of the invasive interventions that can offer symptomatic relief and return of function.

An evidence-based review of CGRP mechanisms in the propagation of chronic visceral pain.

Chronic pain is typically defined as pain that persists after acute tissue damage and inflammation or as pain that follows a chronic disease process and lasts more than three months. Because of its debilitating impact on the quality of life of patients, recent research aims to investigate the mechanisms behind nociception to discover novel therapeutic agents to alleviate pain. One such target is the neuropeptide calcitonin gene-related peptide (CGRP), which has shown to play an integral role in migraine pathophysiology. Effective treatments of migraines with CGRP antagonists have stimulated our efforts toward checking a possible involvement of CGRP in nonheadache pain conditions such as hypertension, congestive heart failure, Alzheimer's disease, and vascular ischemia. Here, we provide a brief overview of chronic pain, with a particular emphasis on the role of CGRP as a fundamental mediator of nociceptive pain as well as a target for novel therapeutic agents.