Decompression and collagen wrapping of a fibrolipomatous hamartoma of the median nerve: a new approach for a rare and difficult problem.

Fibrolipomatous hamartoma is a rare benign slow growing fibrofatty tumor of peripheral nerves of unknown etiology. Clinical presentation may mimic carpal tunnel syndrome when involving the median nerve. We present a case of FLH of the median nerve in a 59-year-old female treated with decompression and collagen nerve wrapping.

Tumor cell-based liquid biopsy using high-throughput microfluidic enrichment of entire leukapheresis product.

Circulating Tumor Cells (CTCs), interrogated by sampling blood from patients with cancer, contain multiple analytes, including intact RNA, high molecular weight DNA, proteins, and metabolic markers. However, the clinical utility of tumor cell-based liquid biopsy has been limited since CTCs are very rare, and current technologies cannot process the blood volumes required to isolate a sufficient number of tumor cells for in-depth assays. We previously described a high-throughput microfluidic prototype utilizing high-flow channels and amplification of cell sorting forces through magnetic lenses. Here, we apply this technology to analyze patient-derived leukapheresis products, interrogating a mean blood volume of 5.83 liters from patients with metastatic cancer, with a median of 2,799 CTCs purified per patient. Isolation of many CTCs from individual patients enables characterization of their morphological and molecular heterogeneity, including cell and nuclear size and RNA expression. It also allows robust detection of gene copy number variation, a definitive cancer marker with potential diagnostic applications. High-volume microfluidic enrichment of CTCs constitutes a new dimension in liquid biopsies.

Case Presentation: Functional Assessment of a CASR Variant Identified in a Patient with Hypercalcaemia Confirms Familial Hypocalciuric Hypercalcaemia in the Patient and a Sister Previously Misdiagnosed with Primary Hyperparathyroidism.

Background: Primary hyperparathyroidism (PHPT) and familial hypocalciuric hypercalcaemia (FHH) are common causes of hypercalcaemia. Patients are mostly asymptomatic in the case of FHH and often so in the case of PHPT. In addition, biochemical parameters show considerable overlap, making differential diagnosis difficult. Genetic screening for inactivating variants in the calcium-sensing receptor (CASR) gene that are causative of FHH assists with the diagnosis since such variants are not generally associated with PHPT. However, novel CASR variants must undergo functional assessment before they can be definitively assigned a causative role in FHH. Case Presentations. We describe a 73-year-old female (patient A) who presented with mild parathyroid hormone (PTH)-dependent hypercalcaemia and a history of osteoporosis. Family history revealed that her sister (patient B) had presented a decade earlier with symptoms of PHPT including a history of mild hypercalcaemia and multiple renal calculi, prompting parathyroid surgery. However, a subtotal parathyroidectomy did not resolve her hypercalcaemia long term. On this basis, genetic screening was performed on patient A. This identified a heterozygous variant in the CASR, NM_000388.4:c.T101C: p.Leu34Pro (L34P). Functional analysis showed that the L34P variant was unable to produce mature, dimerized receptor and did not respond to Ca++ ions. Adopting American College of Medical Genetics-based guidelines, the variant was classified as 'Pathogenic (II)'. Patient B was subsequently found to carry the L34P variant heterozygously, confirming a diagnosis of FHH, not PHPT. Conclusion: This study shows the importance of examining patient's family history in providing clues to the diagnosis in isolated cases of hypercalcaemia. In this case, history of a sister's unsuccessful parathyroidectomy prompted genetic screening in a patient who might otherwise have undergone inappropriate parathyroid surgery. Screening detected an inactivating CASR variant, firming up a diagnosis of FHH. These studies reaffirm the requirement for functionally assessing novel CASR variants prior to assigning causality to FHH.

Hyperthyroidism.

Thyrotoxicosis causes a variety of symptoms and adverse health outcomes. Hyperthyroidism refers to increased thyroid hormone synthesis and secretion, most commonly from Graves' disease or toxic nodular goitre, whereas thyroiditis (typically autoimmune, viral, or drug induced) causes thyrotoxicosis without hyperthyroidism. The diagnosis is based on suppressed serum concentrations of thyroid-stimulating hormone (TSH), accompanied by free thyroxine and total or free tri-iodothyronine concentrations, which are raised (overt hyperthyroidism) or within range (subclinical hyperthyroidism). The underlying cause is determined by clinical assessment, detection of TSH-receptor antibodies and, if necessary, radionuclide thyroid scintigraphy. Treatment options for hyperthyroidism include antithyroid drugs, radioactive iodine, and thyroidectomy, whereas thyroiditis is managed symptomatically or with glucocorticoid therapy. In Graves' disease, first-line treatment is a 12-18-month course of antithyroid drugs, whereas for goitre, radioactive iodine or surgery are preferred for toxic nodules or goitres. Evidence also supports long-term treatment with antithyroid drugs as an option for patients with Graves' disease and toxic nodular goitre.

Insulinoma Presenting With Postprandial Hypoglycemia in a Pregnant Woman With MEN-1.

Insulinomas are rare insulin-secreting tumors of pancreatic origin that cause hypoglycemia and can be associated with multiple endocrine neoplasia type 1 (MEN1). While rare, they are the most common cause of hypoglycemia related to endogenous hyperinsulinism. A 28-year-old woman with known MEN1 presented with postprandial hypoglycemia in the second trimester of pregnancy. Prior to her presentation she was known to have several pancreatic neuroendocrine tumors that had been stable on serial imaging, but no history of hypoglycemia. She was managed with dietary intervention during pregnancy and gave birth to a healthy baby at 37 weeks' gestation. After pregnancy, hypoglycemia initially resolved, but then recurred at 8 months post partum. Magnetic resonance imaging showed several pancreatic neoplasms with the largest lesion measuring 29 mm in the pancreatic tail, unchanged from previous imaging. After localization with a selective arterial calcium stimulation test, the patient underwent successful distal pancreatectomy with resolution of symptoms. This case is unusual in that her initial presentation was during pregnancy, she had predominantly postprandial rather than fasting hypoglycemia, and her symptoms remitted for several months after delivery. Key learning points are to have a low index of suspicion for an insulinoma when there is a history of MEN1 and the need for a pragmatic approach to diagnosis and treatment during pregnancy.

Three Cases of Non-islet Cell Tumor Hypoglycemia Highlighting Efficacy of Glucocorticoid Treatment.

Non-islet cell tumor hypoglycemia (NICTH) is a rarely encountered cause of hypoglycemia. It is most often caused by tumor secretion of precursor insulin-like growth factor-2 (IGF-2) which, in high concentrations, binds to insulin receptors exerting insulin-like metabolic effects. It is often associated with mesenchymal and hepatic tumors. We describe 3 cases of NICTH: a 60-year-old man with an unresectable pelvic sarcoma and two women ages 43 and 57 with metastatic hemangiopericytoma. Biochemical assessment identified hypoglycemia associated with suppressed insulin, c-peptide, and beta-hydroxybutyrate levels. Each patient was treated with oral glucocorticoids, which effectively prevented recurrence of hypoglycemia and this effect was sustained long-term. These cases highlight a rarely encountered but important cause of hypoglycemia and demonstrate the long-term efficacy of glucocorticoid treatment in preventing hypoglycemia in cases of NICTH related to surgically unresectable tumors.

Orthopaedic knee scooter-related injury: prevalence and patient safety perception in a prospective cohort with exploratory risk factor analysis.

BACKGROUND: There is a paucity of research investigating the harms associated with orthopaedic knee scooter (OKS) use and patient safety perceptions. This prospective study aimed to define the prevalence of OKS-related injuries, describe the patient perceptions of OKS safety, and identify potential risk factors. METHODS: This study was conducted at a single foot and ankle fellowship-trained surgeon's community-based clinic from 6/2020 to 4/2021 and enrolled 134 patients. Our primary outcome was an OKS-related event (injury or fall) and informed an a priori power analysis. Point estimate of association magnitude was calculated as an odds ratio (OR) for statistically and clinically significant associations. RESULTS: There were 118 (88%) patients eligible for analysis; fourteen enrolled patients did not use OKS, and two withdrew. The prevalence of patient falls was 37% (44/118), and the prevalence of patient injury was 15% (18/118). Four percent of patients would not recommend OKS and 8% would not use an OKS again. Sedentary lifestyle increased risk (OR = 4.67, 1.52-14.35 95 CI) for OKS-related injury. CONCLUSIONS: Despite a high prevalence of patient falls (37%), there is a low prevalence of injury (15%) and a favorable perception of OKS safety. Sedentary lifestyles may be a risk factor for OKS-related injury and should be considered in the development of a risk model.

The optimal healthy ranges of thyroid function defined by the risk of cardiovascular disease and mortality: systematic review and individual participant data meta-analysis.

BACKGROUND: Reference intervals of thyroid-stimulating hormone (TSH) and free thyroxine (FT4) are statistically defined by the 2·5-97·5th percentiles, without accounting for potential risk of clinical outcomes. We aimed to define the optimal healthy ranges of TSH and FT4 based on the risk of cardiovascular disease and mortality. METHODS: This systematic review and individual participant data (IPD) meta-analysis identified eligible prospective cohorts through the Thyroid Studies Collaboration, supplemented with a systematic search via Embase, MEDLINE (Ovid), Web of science, the Cochrane Central Register of Controlled Trials, and Google Scholar from Jan 1, 2011, to Feb 12, 2017 with an updated search to Oct 13, 2022 (cohorts found in the second search were not included in the IPD). We included cohorts that collected TSH or FT4, and cardiovascular outcomes or mortality for adults (aged ≥18 years). We excluded cohorts that included solely pregnant women, individuals with overt thyroid diseases, and individuals with cardiovascular disease. We contacted the study investigators of eligible cohorts to provide IPD on demographics, TSH, FT4, thyroid peroxidase antibodies, history of cardiovascular disease and risk factors, medication use, cardiovascular disease events, cardiovascular disease mortality, and all-cause mortality. The primary outcome was a composite outcome including cardiovascular disease events (coronary heart disease, stroke, and heart failure) and all-cause mortality. Secondary outcomes were the separate assessment of cardiovascular disease events, all-cause mortality, and cardiovascular disease mortality. We performed one-step (cohort-stratified Cox models) and two-step (random-effects models) meta-analyses adjusting for age, sex, smoking, systolic blood pressure, diabetes, and total cholesterol. The study was registered with PROSPERO, CRD42017057576. FINDINGS: We identified 3935 studies, of which 53 cohorts fulfilled the inclusion criteria and 26 cohorts agreed to participate. We included IPD on 134 346 participants with a median age of 59 years (range 18-106) at baseline. There was a J-shaped association of FT4 with the composite outcome and secondary outcomes, with the 20th (median 13·5 pmol/L [IQR 11·2-13·9]) to 40th percentiles (median 14·8 pmol/L [12·3-15·0]) conveying the lowest risk. Compared with the 20-40th percentiles, the age-adjusted and sex-adjusted hazard ratio (HR) for FT4 in the 80-100th percentiles was 1·20 (95% CI 1·11-1·31) for the composite outcome, 1·34 (1·20-1·49) for all-cause mortality, 1·57 (1·31-1·89) for cardiovascular disease mortality, and 1·22 (1·11-1·33) for cardiovascular disease events. In individuals aged 70 years and older, the 10-year absolute risk of composite outcome increased over 5% for women with FT4 greater than the 85th percentile (median 17·6 pmol/L [IQR 15·0-18·3]), and men with FT4 greater than the 75th percentile (16·7 pmol/L [14·0-17·4]). Non-linear associations were identified for TSH, with the 60th (median 1·90 mIU/L [IQR 1·68-2·25]) to 80th percentiles (2·90 mIU/L [2·41-3·32]) associated with the lowest risk of cardiovascular disease and mortality. Compared with the 60-80th percentiles, the age-adjusted and sex-adjusted HR of TSH in the 0-20th percentiles was 1·07 (95% CI 1·02-1·12) for the composite outcome, 1·09 (1·05-1·14) for all-cause mortality, and 1·07 (0·99-1·16) for cardiovascular disease mortality. INTERPRETATION: There was a J-shaped association of FT4 with cardiovascular disease and mortality. Low concentrations of TSH were associated with a higher risk of all-cause mortality and cardiovascular disease mortality. The 20-40th percentiles of FT4 and the 60-80th percentiles of TSH could represent the optimal healthy ranges of thyroid function based on the risk of cardiovascular disease and mortality, with more than 5% increase of 10-year composite risk identified for FT4 greater than the 85th percentile in women and men older than 70 years. We propose a feasible approach to establish the optimal healthy ranges of thyroid function, allowing for better identification of individuals with a higher risk of thyroid-related outcomes. FUNDING: None.

The impact of Three-Dimensional Gait Analysis in adults with pathological gait on management recommendations.

BACKGROUND: Three-Dimensional Gait Analysis (3DGA) is a gold standard tool that can help identify pathological components of walking patterns. It has been well established that this tool influences the treatment decision making of clinicians treating paediatric patients with Cerebral Palsy, but it has not been established whether this tool changes decision making of clinicians treating adults with complex pathological gait. RESEARCH QUESTION: To investigate the impact of pre-treatment 3DGA on treatment plans and management of adults with complex pathological gait. METHOD: This retrospective audit examined the medical records of 87 patients undergoing pre-treatment 3DGA between 2014 and 2019. The review collected treatment plans from the initial referral, the post-gait analysis multidisciplinary report, and post-intervention progress notes with consistencies and differences noted throughout the care pathway. RESULTS: Treatment plans of patients were altered in 80 % (N = 32) of patients following 3DGA assessment and recommendations. These treatment plan alterations included a change in surgery or avoidance of surgery, changes in orthosis prescriptions, casting or rehabilitation; and administration or changes in administration of Botulinum Neurotoxin (BoNT-A). In 47 % (N = 15) of cases the change in plans represented a de-escalation in intervention requirements (e.g. BoNT-A in lieu of surgical intervention), and in 31 % (N = 10) the change in plans represented an escalation in intervention requirements (e.g. requirement for surgery). These changes in treatment plans were either fully or partly enacted by the referring consultant in 86 % of cases. SIGNIFICANCE: Pre-treatment 3DGA impacts the management of adult patients with complex pathological gait and facilitates patients potentially avoiding unnecessary interventions. Further investigation is needed to determine the cost effectiveness of 3DGA in this population and the impact of pre-treatment 3DGA on management outcomes.

Orellanine: From Fungal Origin to a Potential Future Cancer Treatment.

Fungal metabolites represent an underutilized resource in the development of novel anticancer drugs. This review will focus on the promising fungal nephrotoxin orellanine, found in mushrooms including Cortinarius orellanus (Fools webcap). Emphasis will be placed on its historical significance, structural features, and associated toxicomechanics. Chromatographic methods for analysis of the compound and its metabolites, its synthesis, and chemotherapeutic potential are also discussed. Although orellanine's exceptional selectivity for proximal tubular cells is well documented, the mechanics of its toxicity in kidney tissue remains disputed. Here, the most commonly proposed hypotheses are detailed in the context of the molecule's structure, the symptoms seen following ingestion, and its characteristic prolonged latency period. Chromatographic analysis of orellanine and its related substances remains challenging, while biological evaluation of the compound is complicated by uncertainty regarding the role of active metabolites. This has limited efforts to structurally refine the molecule; despite numerous established methods for its synthesis, there is minimal published material on how orellanine's structure might be optimized for therapeutic use. Despite these obstacles, orellanine has generated promising data in preclinical studies of metastatic clear cell renal cell carcinoma, leading to the early 2022 announcement of phase I/II trials in humans.

MR Imaging-Based In Vivo Macrophage Imaging to Monitor Immune Response after Radiofrequency Ablation of the Liver.

PURPOSE: To establish molecular magnetic resonance (MR) imaging instruments for in vivo characterization of the immune response to hepatic radiofrequency (RF) ablation using cell-specific immunoprobes. MATERIALS AND METHODS: Seventy-two C57BL/6 wild-type mice underwent standardized hepatic RF ablation (70 °C for 5 minutes) to generate a coagulation area measuring 6-7 mm in diameter. CD68+ macrophage periablational infiltration was characterized with immunohistochemistry 24 hours, 72 hours, 7 days, and 14 days after ablation (n = 24). Twenty-one mice were subjected to a dose-escalation study with either 10, 15, 30, or 60 mg/kg of rhodamine-labeled superparamagnetic iron oxide nanoparticles (SPIONs) or 2.4, 1.2, or 0.6 mg/kg of gadolinium-160 (160Gd)-labeled CD68 antibody for assessment of the optimal in vivo dose of contrast agent. MR imaging experiments included 9 mice, each receiving 10-mg/kg SPIONs to visualize phagocytes using T2∗-weighted imaging in a horizontal-bore 9.4-T MR imaging scanner, 160Gd-CD68 for T1-weighted MR imaging of macrophages, or 0.1-mmol/kg intravenous gadoterate (control group). Radiological-pathological correlation included Prussian blue staining, rhodamine immunofluorescence, imaging mass cytometry, and immunohistochemistry. RESULTS: RF ablation-induced periablational infiltration (206.92 µm ± 12.2) of CD68+ macrophages peaked at 7 days after ablation (P < .01) compared with the untreated lobe. T2∗-weighted MR imaging with SPION contrast demonstrated curvilinear T2∗ signal in the transitional zone (TZ) (186 µm ± 16.9), corresponsing to Iron Prussian blue staining. T1-weighted MR imaging with 160Gd-CD68 antibody showed curvilinear signal in the TZ (164 µm ± 3.6) corresponding to imaging mass cytometry. CONCLUSIONS: Both SPION-enhanced T2∗-weighted and 160Gd-enhanced T1-weighted MR imaging allow for in vivo monitoring of macrophages after RF ablation, demonstrating the feasibility of this model to investigate local immune responses.

Clinical Reasoning: A 23-Year-Old Woman Presenting With Cognitive Impairment and Gait Disturbance.

Metachromatic leukodystrophy (MLD) is a rare inherited lysosomal disorder. The condition progresses relentlessly, with severe disability typically established within 6-14 years of symptom onset. There is no cure, and limited treatment options are available to slow disease progression. We describe the case of a 23-year-old woman with forgetfulness, unsteady gait, and falls. Neurologic examination revealed intermittent dystonic posturing of the right upper and lower limb when walking. The Addenbrooke's Cognitive Examination (ACE) score was 70/100. MRI sequences demonstrated frontal-predominant atrophy and extensive white matter hyperintensity. Differential diagnoses such as autoimmune, inflammatory, and neoplastic diseases were excluded, and a genetic diagnosis was considered. Lysosomal enzyme testing showed low arylsulfatase with elevated urinary sulfatides, and genetic testing revealed a homozygous pathogenic mutation in the ARSA gene securing a diagnosis of adult-onset MLD. A male sibling also had early cognitive impairment and was found to have the same mutation. Hematopoietic stem cell transplantation (HSCT) was offered after discussion with experts. The male sibling died of multiple complications after HSCT. The index patient is now 24 months after HSCT, and disease progression has halted. This case highlights the challenges in the accurate diagnosis of adult-onset leukoencephalopathies and explores potential treatment strategies. A stepwise approach to the differential diagnosis of white matter diseases is demonstrated. HSCT may be an effective treatment, but the significant complication rate needs to be carefully considered.

Mitigating Spinal Cord Stimulator Lead Migration Complications in Minimally Invasive Spine Surgery: Technical Note.

Spinal Cord Stimulators (SCS) are a nonpharmacologic chronic pain management treatment modality that is well-validated and cost-effective within the surgeon's armamentarium. The reported complication rates are between 5.3% to 40%, most commonly secondary to mechanical hardware failure. The most common mechanical complication is lead migration, which necessitates second surgery. The purpose of this technical note is to describe a minimally invasive spine surgery (MISS) implantation technique we believe to be more resilient to lead migration. We present a stepwise technique for SCS implantation with a maxillofacial screw and washer failsafe.

Selective Delivery of Clinically Approved Tubulin Binding Agents through Covalent Conjugation to an Active Targeting Moiety.

The efficacy and tolerability of tubulin binding agents are hampered by their low specificity for cancer cells like most clinically used anticancer agents. To improve specificity, tubulin binding agents have been covalently conjugated to agents that target cancer cells to give actively targeted drug conjugates. These conjugates are designed to increase uptake of the drug by cancer cells while having limited uptake by normal cells, thereby improving efficacy and tolerability. Approaches used include an attachment to small molecules, polysaccharides, peptides, proteins, and antibodies that exploit the overexpression of receptors for these substances. Antibody targeted strategies have been the most successful to date, with six such examples having gained clinical approval. Many other conjugate types, especially those targeting the folate receptor, have shown promising efficacy and toxicity profiles in pre-clinical models and in early-stage clinical studies. Presented herein is a discussion of the success or otherwise of the recent strategies used to form these actively targeted conjugates.

CD5 + Gamma Delta T-Cell Lymphoproliferative Disorder/Lymphoma Without Cytotoxic Granules in the Skin.

ABSTRACT: We report a case of an unusual and aggressive gamma delta T-cell lymphoproliferative disorder/lymphoma presenting in the skin that lacked the expected cytotoxic markers and had increased expression of CD5, CD20, CD79a, CD30, and PD-1 without CD56. Monoclonal TCR-γ gene rearrangement was identified. A computed tomography scan of the chest, abdomen, and pelvis revealed a 7.7-cm soft-tissue inguinal mass and prominent retroperitoneal and pelvic lymphadenopathy, without hepatosplenomegaly. Flow cytometry finding on peripheral blood was normal. The clinical, morphologic, and immunophenotypic features of this case defy the current World Health Organization and European Organization for Research and Treatment of Cancer classifications, and a similar case has not been reported previously.

Clinical outcomes in the surgical management of ankle fractures: A systematic review and meta-analysis of fibular intramedullary nail fixation vs. open reduction and internal fixation in randomized controlled trials.

BACKGROUND: What level I evidence exists to support the use of FNF for surgical management of ankle fractures in high risk patients? The purpose of this study was to compare clinical outcomes following fibular intramedullary nail fixation (FNF) and open reduction and internal fixation (ORIF) of ankle fractures. METHODS: A systematic review of the current literature was performed according to Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. Certainty of evidence reported according to GRADE (Grading of Recommendations Assessment, Development, and Evaluation). Our primary hypothesis was that patients undergoing FNF procedures to manage an ankle fracture would have significantly higher patient reported outcome scores (PROs) than patients undergoing ORIF. Primary study outcome measures were validated PROs. Secondary outcome measures included complication rate, secondary surgery rate, and bony union. RESULTS: The primary outcome analysis revealed no evidence of a significant effect difference on Olerud and Molander Ankle Score (OMAS) PRO and no evidence of statistical heterogeneity. Secondary outcome analysis revealed a significant 0.30 (0.12-0.74 95CI) relative risk reduction for complications in FNF (P = 0.008). No evidence of an effect difference for bony union. The GRADE certainty of the evidence was rated as low for bone union. No evidence of reporting bias was appreciated. Sensitivity analyses did not significantly alter effect estimates. CONCLUSION: This systematic review and meta-analysis restricted to evidence derived from RCTs revealed that the quality of evidence is reasonably strong and likely sufficient to conclude: (1) there is likely no clinically important difference between FNF and ORIF up to 12 months post-operatively, as defined by OMS (moderate certainty); (2) surgeons may reasonably expect reduced complications in 14 out of every 100 patients treated with FNF (moderate certainty); (3) there is likely no difference in bony union (low certainty). Future studies should investigate more patient-centered outcomes and if short-term findings are durable over time if these findings apply to lower risk populations. LEVEL OF EVIDENCE: Systematic review and meta-analysis of level I evidence.

Association between maternal thyroid function and risk of gestational hypertension and pre-eclampsia: a systematic review and individual-participant data meta-analysis.

BACKGROUND: Adequate maternal thyroid function is important for an uncomplicated pregnancy. Although multiple observational studies have evaluated the association between thyroid dysfunction and hypertensive disorders of pregnancy, the methods and definitions of abnormalities in thyroid function tests were heterogeneous, and the results were conflicting. We aimed to examine the association between abnormalities in thyroid function tests and risk of gestational hypertension and pre-eclampsia. METHODS: In this systematic review and meta-analysis of individual-participant data, we searched MEDLINE (Ovid), Embase, Scopus, and the Cochrane Database of Systematic Reviews from date of inception to Dec 27, 2019, for prospective cohort studies with data on maternal concentrations of thyroid-stimulating hormone (TSH), free thyroxine (FT4), thyroid peroxidase (TPO) antibodies, individually or in combination, as well as on gestational hypertension, pre-eclampsia, or both. We issued open invitations to study authors to participate in the Consortium on Thyroid and Pregnancy and to share the individual-participant data. We excluded participants who had pre-existing thyroid disease or multifetal pregnancy, or were taking medications that affect thyroid function. The primary outcomes were documented gestational hypertension and pre-eclampsia. Individual-participant data were analysed using logistic mixed-effects regression models adjusting for maternal age, BMI, smoking, parity, ethnicity, and gestational age at blood sampling. The study protocol was registered with PROSPERO, CRD42019128585. FINDINGS: We identified 1539 published studies, of which 33 cohorts met the inclusion criteria and 19 cohorts were included after the authors agreed to participate. Our study population comprised 46 528 pregnant women, of whom 39 826 (85·6%) women had sufficient data (TSH and FT4 concentrations and TPO antibody status) to be classified according to their thyroid function status. Of these women, 1275 (3·2%) had subclinical hypothyroidism, 933 (2·3%) had isolated hypothyroxinaemia, 619 (1·6%) had subclinical hyperthyroidism, and 337 (0·8%) had overt hyperthyroidism. Compared with euthyroidism, subclinical hypothyroidism was associated with a higher risk of pre-eclampsia (2·1% vs 3·6%; OR 1·53 [95% CI 1·09-2·15]). Subclinical hyperthyroidism, isolated hypothyroxinaemia, or TPO antibody positivity were not associated with gestational hypertension or pre-eclampsia. In continuous analyses, both a higher and a lower TSH concentration were associated with a higher risk of pre-eclampsia (p=0·0001). FT4 concentrations were not associated with the outcomes measured. INTERPRETATION: Compared with euthyroidism, subclinical hypothyroidism during pregnancy was associated with a higher risk of pre-eclampsia. There was a U-shaped association of TSH with pre-eclampsia. These results quantify the risks of gestational hypertension or pre-eclampsia in women with thyroid function test abnormalities, adding to the total body of evidence on the risk of adverse maternal and fetal outcomes of thyroid dysfunction during pregnancy. These findings have potential implications for defining the optimal treatment target in women treated with levothyroxine during pregnancy, which needs to be assessed in future interventional studies. FUNDING: Arkansas Biosciences Institute and Netherlands Organization for Scientific Research.

Hybridization of green synthesized silver nanoparticles with poly(ethylene glycol) methacrylate and their biomedical applications.

In the present research, a rapid, simple and efficient green method is used for the incorporation of silver nanoparticles (AgNPs) into poly(ethylene glycol) methacrylate (PEGMA) to create biocatalysts with excellent properties for pharmaceutical purpose. In the first phase, Caralluma tuberculata capped AgNPs (Ca-AgNPs) were prepared using green synthetic approach and in the second phase Caralluma tuberculata capped AgNPs were hybridized with poly(ethylene glycol) methacrylate to form PEGMA-AgNPs. Both the virgin (naked or uncapped) and polymer-capped materials were characterized spectroscopically and their results were compared. Fourier transform infrared spectroscopy showed no new peak after the capping procedure, showing that only physical interactions takes place during capping. After PEGMA capping, the spectra of the AgNPs red shifted (from 450 nm to 520 nm) and the overall particle size of AgNPs increased. Catalytic activity of the nanoparticles and hybrid system were tested by choosing the catalytic reduction of 4-nitrophenol (4-NP) as a model reaction. Both synthesized NPs and polymer capped NPs exhibits catalytic activity for the reduction of 4-NP to 4-aminophenol. The polymer hybrid exhibits remarkable antiproliferative, antioxidant, cytotoxic, antidiabetic and antileishmanial activities.

Extracellular pH Mapping as Therapeutic Readout of Drug Delivery in Glioblastoma.

An acidic extracellular space is a hallmark of the tumor microenvironment. Acidosis has been postulated to promote the aggressive and invasive characteristics of tumors and also inhibit the therapeutic response, particularly in the context of novel immunotherapies. Therefore, methods to quantitatively measure the extracellular pH (pHe) are needed. Here we describe a magnetic resonance spectroscopic imaging (MRSI) technique termed Biosensor Imaging of Redundant Deviation in Shifts (BIRDS), which uses the pH-dependent chemical shifts of nonexchangeable protons of lanthanide-based contrast agents to generate quantitative spatial pHe maps. We assess this method in the context of evaluating the acidic pHe and therapeutic response in glioblastoma in rodents, where normalization of the pHe upon therapy can serve as a quantitative readout of successful drug delivery to the tumor.

Challenges in Oncologic Preparedness: A Retrospective Review of Incident Surgical Cancers During Pacific Partnership Missions, 2008-2016.

INTRODUCTION: For over 30 years, the USNS Mercy hospital ship has provided surgical care on multiple humanitarian aid and disaster relief missions. During these missions, surgical support varies according to host nation needs, and the operative treatment of cancer patients remains controversial. We report the number of incidentally discovered surgical oncologic cases treated aboard the USNS Mercy on four missions and discuss challenges regarding oncologic care on these missions. MATERIALS AND METHODS: Between 2008 and 2016, operative cases and surgical pathology results from four multinational humanitarian missions were analyzed according to organ system, patient's geographic location, and diagnosis. Primary outcomes were total number and proportion of malignant cases, analyzed yearly and over all four missions. Secondary outcomes were malignant diagnoses by organ system and host nation health capacities (based on indicators from the WHO). RESULTS: A total of 2,767 operations were performed during 18 port visits in 8 countries in Southeast Asia. In total, 1,193 pathology specimens (surgical biopsies, fine needle aspirations, etc.) were obtained. Overall malignancy rate across all organ systems was 9%. Yearly malignancy rates ranged from 2% to 13%. The highest malignancy rates were found in thyroid (33%), breast (20%), and parotid and salivary gland cases (19%). All host nations had operational strategies for cancer in place (n = 8, 100%), but few had national infrastructures to treat noncommunicable diseases (n = 2, 25%). CONCLUSIONS: Despite current policies to screen out cancer patients on USNS Mercy missions, 9% of surgical biopsies were malignant. Cancer management during these missions presents a unique challenge because of limited resources for surgery, chemoradiotherapy, and follow-up care. Contingency plans must be considered to provide completion of care for these patients whose cancers are discovered incidentally. Furthermore, an understanding of host nation capabilities in relation to medical and surgical care is crucial to providing treatment in resource-limited areas.