Withdrawal of bevacizumab is associated with rebound growth of vestibular schwannomas in neurofibromatosis type 2-related schwannomatosis patients.

Background: Neurofibromatosis type 2 (NF2)-related schwannomatosis is an autosomal dominant tumor-predisposition syndrome characterized by bilateral vestibular schwannomas (VS). In patients with VS associated with NF2, vascular endothelial growth factor A inhibitor, bevacizumab, is a systemic treatment option. The aim of this study is to retrospectively evaluate NF2 patient responses to bevacizumab on VS growth and symptom progression. Methods: This is a retrospective analysis of patients seen at the Mayo Clinic Rochester Multidisciplinary NF2 Clinic. Results: Out of 76 patients with NF2 evaluated between 2020 and 2022, we identified 19 that received treatment with bevacizumab. Thirteen of these patients discontinued bevacizumab after median treatment duration of 12.2 months. The remaining 6 patients are currently receiving bevacizumab treatment for a median duration of 9.4 months as of March, 2023. Fifteen patients had evaluable brain MRI data, which demonstrated partial responses in 5 patients, stable disease in 8, and progression in 2. Within 6 months of bevacizumab discontinuation, 5 patients had rebound growth of their VS greater than 20% from their previous tumor volume, while 3 did not. Three patients with rebound growth went on to have surgery or irradiation for VS management. Conclusions: Our single-institution experience confirms prior studies that bevacizumab can control progression of VS and symptoms associated with VS growth. However, we note that there is the potential for rapid VS growth following bevacizumab discontinuation, for which we propose heightened surveillance imaging and symptom monitoring for at least 6 months upon stopping anti-VEGF therapy.

An Assessment of Earth's Climate Sensitivity Using Multiple Lines of Evidence.

We assess evidence relevant to Earth's equilibrium climate sensitivity per doubling of atmospheric CO2, characterized by an effective sensitivity S. This evidence includes feedback process understanding, the historical climate record, and the paleoclimate record. An S value lower than 2 K is difficult to reconcile with any of the three lines of evidence. The amount of cooling during the Last Glacial Maximum provides strong evidence against values of S greater than 4.5 K. Other lines of evidence in combination also show that this is relatively unlikely. We use a Bayesian approach to produce a probability density function (PDF) for S given all the evidence, including tests of robustness to difficult-to-quantify uncertainties and different priors. The 66% range is 2.6-3.9 K for our Baseline calculation and remains within 2.3-4.5 K under the robustness tests; corresponding 5-95% ranges are 2.3-4.7 K, bounded by 2.0-5.7 K (although such high-confidence ranges should be regarded more cautiously). This indicates a stronger constraint on S than reported in past assessments, by lifting the low end of the range. This narrowing occurs because the three lines of evidence agree and are judged to be largely independent and because of greater confidence in understanding feedback processes and in combining evidence. We identify promising avenues for further narrowing the range in S, in particular using comprehensive models and process understanding to address limitations in the traditional forcing-feedback paradigm for interpreting past changes.

Influence of maternal protein restriction in primiparous heifers during mid- and/or late-gestation on meat quality and fatty acid profile of progeny.

The objective of this study was to evaluate the influence of metabolizable protein (MP) restriction in mid- and/or late-gestation on meat quality characteristics of progeny. Heifers were assigned to 2 levels of dietary protein (control [CON], 102% of MP requirements; or restricted [RES], 80% of MP requirements) at 2 stages of gestation (mid-gestation [MID] and late-gestation [LATE]) in a Balaam's Design crossover treatment structure resulting in 4 treatment combinations (CON-CON, CON-RES, RES-CON, RES-RES). A carryover effect of MID MP treatment on LATE CON indicated CON-CON steaks were more tender (P < .001) than RES CON. Mid-gestation restriction resulted in progeny with increased (P < .05) carcass water, soft tissue moisture, and decreased soft tissue fat percentage compared with progeny from dams receiving MID CON. Reduced maternal MP also differentially influenced the fatty acid profiles of progeny. Results suggest it is possible for progeny to overcome a moderate gestational MP restriction with minimal impacts on carcass composition or meat characteristics.

Concomitant HIV infection in newly diagnosed multiple myeloma patients is hard to recognise and should be tested for routinely in areas of high endemicity.

BACKGROUND: Over the past three decades much has changed in the treatment and outcomes of patients suffering concurrently from both multiple myeloma (MM) and HIV. While the prevalence of MM appears to be higher in HIV-positive individuals than in those who are uninfected, early recognition of patients suffering from both diseases is difficult and little information is available on their demographics and clinical presentation. OBJECTIVE: To compare the presenting features of HIV-positive patients diagnosed with MM with those of HIV-negative patients. METHODS: A single-centre, retrospective cohort study included 16 HIV-positive and 73 HIV-negative patients diagnosed with MM, in order to compare variables related to the clinical presentation of both conditions. RESULTS: HIV-positive patients presented with MM at a significantly younger age, and had fewer osteolytic lesions, less renal impairment and lower neutrophil counts. Disease stage, gender, pathological fractures, bone marrow plasmacytosis, plasmacytomas and lymphocyte counts were comparable, emphasising the difficulty of identifying these patients. The HIV-positive patients had relatively high CD4 counts and a low prevalence of abnormal Freelite kappa/lambda ratios. All HIV-positive patients presented with paraproteins of the immunoglobulin G (IgG) type, implying a possible relationship between MM and an IgG response to HIV antigens. CONCLUSIONS: On the basis of our findings and literature on the treatment of both diseases, we suggest that HIV be tested for routinely in younger MM patients, especially in areas with a high prevalence of HIV. The integration of our results into the sparse knowledge on the role of HIV infection-related MM provides possible new insights into the interaction between these diseases.

Effect of nursing-calf implant timing on growth performance and carcass characteristics.

The objective of this study was to compare pre- and postweaning growth performance, carcass characteristics, and meat quality attributes of calves that did not receive an implant or were implanted early or late in the nursing period. Crossbred steer calves ( = 135) were stratified by birth date and birth weight and randomly assigned to the following implant treatments: control (CON; no preweaning implant), 58 d (EARLY; 36 mg zeranol, administered at an average of 58 ± 13 d of age), and 121 d (LATE; 36 mg zeranol, administered at an average 121 ± 13 d of age). After weaning, steers were blocked by initial feed yard BW to 15 pens (5 pens/treatment and 9 steers/pen). All steers were implanted on d 21 after arrival at the feed yard and again on d 108 of finishing. Steer BW and ultrasound assessment of rib eye area (uREA), rib fat thickness (uRFT), and percent intramuscular fat (uIMF) were collected when implants were administered, at weaning, and on harvest day. Carcass measurements included HCW, rib eye area (REA), 12th-rib fat thickness (FT), and marbling score. Objective color (L*, a*, and b*) was recorded, and a 3.8-cm strip loin section was removed from both sides of each carcass and portioned into 2.54-cm steaks that were aged for 3 or 14 d for analysis of cook loss and Warner-Bratzler shear force (WBSF). The remaining portion of each sample was used for analysis of moisture and crude fat. Steer BW, ADG, and G:F did not differ among treatments ( > 0.05). Steers implanted in the EARLY treatment had a greater ( < 0.05) cumulative DMI than CON but were not different from steers implanted in the LATE treatment. Ultrasound REA and uRFT (averaged across all collection days) did not differ ( > 0.05); however, steers on the CON treatment had a greater ( ≤ 0.05) percent uIMF than EARLY implanted steers, whereas steers receiving the LATE implant were intermediate and not different from the other treatments. Hot carcass weight, REA, FT, USDA yield grade, marbling score, and objective color did not differ ( > 0.05) among treatments. The proportion of steers in each USDA yield and quality grade was similar ( > 0.05) among treatments, and no differences were detected for total carcass value or price per 45.4 kg (hundredweight; > 0.05). Treatment did not influence ( > 0.05) percent cook loss, crude fat, moisture, or WBSF. In conclusion, administering a nursing implant, regardless of timing, did not influence live performance, carcass characteristics, or meat quality of steers fed in this study.

An audit of the use of platelet transfusions at Universitas Academic Hospital, Bloemfontein, South Africa.

An audit was performed at a tertiary hospital in Bloemfontein, South Africa, to establish whether clinicians adhered to local platelet transfusion guidelines. The audit showed poor compliance with local guidelines, with 34% of platelet transfusions not aligned with guidelines and 29.9% of transfusions administered to patients with platelet counts of ≥ 150 × 10(9)/L. When compared to medical disciplines, surgical disciplines tended significantly more to transfuse platelets inappropriately (17.1% and 53.7%, respectively; p < 0.0001). Documentation was poor and in 48.4% of orders for platelets, the indication for the platelet transfusion was not clearly stated. Considerable cost could be avoided with improved adherence to guidelines. This study emphasises the need for improving education in transfusion medicine amongst medical doctors. It is hoped that the information gleaned from this study would assist in the design of educational programmes in transfusion medicine as we attempt to close the existing gaps in knowledge and skills in the field, while ensuring that blood is transfused in a cost-effective and appropriate manner.

Patients' recall and perceptions regarding consent to blood transfusion at Universitas Academic Hospital, Bloemfontein, South Africa.

We studied the recall and perceptions of transfused patients at a single centre. Fifty-three patients were included. In 11 (20.8%) cases, no written informed consent document could be traced. Four patients who had informed consent documents in their records had no recollection of the consent process. Approximately 11% of patients stated that the consent process was performed using unfamiliar terms. When compared to Caucasian and mixed race respondents, more African respondents (83%) would have preferred the presence of a family member (p < 0.01). Although not all the patients experienced the informed consent positively, it did not impact on their perception of the blood transfusion itself.

Pityriasis rotunda as an incidental paraneoplastic finding in two patients with multiple myeloma.

Pityriasis rotunda (PR) is an uncommon chronic dermatosis, which may be idiopathic or may be associated with infections or malignancy. We describe the clinical and biochemical findings of two patients with multiple myeloma, who were incidentally diagnosed with PR, and detail the clinical conditions with which this rare paraneoplastic phenomenon may be associated. Although PR is a rare condition, it may be found as a paraneoplastic phenomenon in a range of conditions, and thus should be recognised as an important clinical sign.

The prevalence of patellar tendinopathy in elite academy rugby: a clinical and imaging study.

OBJECTIVES: Patellar tendinopathy (PT) is a challenging condition with variable outcomes. It is not commonly reported in rugby. This study was undertaken to evaluate the prevalence of PT in elite academy rugby. DESIGN: Cross-sectional study. METHODS: Members of the rugby academies in Ireland were evaluated using blinded, standardised clinical examination, self reported questionnaires and ultrasound. Anthropometrics were examined, body mass and fat% were measured by bio-impedance. The Cincinnati Sports Activity Scale, established activity levels. The VISA-P scale evaluated symptoms. Ultrasound examination established tendon thickness, echogenicity and homogeneity including focal areas of tendinopathy in both transverse and longitudinal planes. Studies were reviewed and graded by two musculoskeletal radiologists. Statistical analysis was performed using PASW 18 and CIA software. Significance was set at p<.05. RESULTS: Thirty individuals (36.1%) had US abnormalities identified with 38 abnormal tendons. The abnormalities seen were microcalculi (44.7%; N=17), thickened tendons ± large areas of cystic degenerative change (26.3%) and macrocalculi or large hypoechoic areas (28.9%; N=11). Eleven individuals (13.3%) fulfilled the clinical diagnosis of PT based on clinical examination. Combining both US and clinical the prevalence of PT in this cohort was 9.6% (N=8). There was a statistically significant difference between the prevalence of patellar tendinopathy based upon US findings (p=.027) and the combination of both clinical examination and US (p=.044) in different training academies. CONCLUSIONS: This work shows that PT is a relatively common injury in elite academy rugby players and that training practices may contribute to its development.

Cooling an acute muscle injury: can basic scientific theory translate into the clinical setting?

Ice is commonly used after acute muscle strains but there are no clinical studies of its effectiveness. By comparison, there are a number of basic scientific studies on animals which show that applying ice after muscle injury has a consistent effect on a number of important cellular and physiological events relating to recovery. Some of these effects may be temperature dependant; most animal studies induce significant reductions in muscle temperature at the injury site. The aim of this short report was to consider the cooling magnitudes likely in human models of muscle injury and to discuss its relevance to the clinical setting. Current best evidence shows that muscle temperature reductions in humans are moderate in comparison to most animal models, limiting direct translation to the clinical setting. Further important clinical questions arise when we consider the heterogenous nature of muscle injury in terms of injury type, depth and insulating adipose thickness. Contrary to current practice, it is unlikely that a 'panacea' cooling dose or duration exists in the clinical setting. Clinicians should consider that in extreme circumstances of muscle strain (eg, deep injury with high levels of adipose thickness around the injury site), the clinical effectiveness of cooling may be significantly reduced.

Guidelines for the treatment of myelodysplastic syndromes (MDS) in South Africa.

INTRODUCTION: Myelodysplastic syndromes (MDS) encompass a heterogeneous group of clonal haematopoietic disorders characterised by chronic and progressive cytopenias resulting from ineffective haematopoiesis. Treatment is complicated by differences in disease mechanisms in different subgroups, variable clinical phenotypes and risk of progression to acute myeloid leukaemia. RATIONALE: Changes in disease classification, prognostic scoring systems, the availability of novel treatment options and the absence of South African guidelines for the diagnosis and management of these complex disorders underpinned the need for the development of these recommendations. METHODS: These recommendations are based on the opinion of a number of experts in the field from the laboratory as well as clinical settings and came from both the private and institutional academic environments. The most recent literature as well as available guidelines from other countries were discussed and debated at a number of different meetings held over a 2-year period. RESULTS: A comprehensive set of recommendations was developed focusing on risk stratification, supportive management and specific treatment. Novel agents and their indications are discussed and recommendations are made based on best available evidence and taking into account the availability of treatments in South Africa. CONCLUSION: Correct diagnosis, risk stratification and appropriate therapeutic choices are the cornerstones of success in the management of patients with myelodysplastic syndromes.

A methodology for probabilistic predictions of regional climate change from perturbed physics ensembles.

A methodology is described for probabilistic predictions of future climate. This is based on a set of ensemble simulations of equilibrium and time-dependent changes, carried out by perturbing poorly constrained parameters controlling key physical and biogeochemical processes in the HadCM3 coupled ocean-atmosphere global climate model. These (ongoing) experiments allow quantification of the effects of earth system modelling uncertainties and internal climate variability on feedbacks likely to exert a significant influence on twenty-first century climate at large regional scales. A further ensemble of regional climate simulations at 25km resolution is being produced for Europe, allowing the specification of probabilistic predictions at spatial scales required for studies of climate impacts. The ensemble simulations are processed using a set of statistical procedures, the centrepiece of which is a Bayesian statistical framework designed for use with complex but imperfect models. This supports the generation of probabilities constrained by a wide range of observational metrics, and also by expert-specified prior distributions defining the model parameter space. The Bayesian framework also accounts for additional uncertainty introduced by structural modelling errors, which are estimated using our ensembles to predict the results of alternative climate models containing different structural assumptions. This facilitates the generation of probabilistic predictions combining information from perturbed physics and multi-model ensemble simulations. The methodology makes extensive use of emulation and scaling techniques trained on climate model results. These are used to sample the equilibrium response to doubled carbon dioxide at any required point in the parameter space of surface and atmospheric processes, to sample time-dependent changes by combining this information with ensembles sampling uncertainties in the transient response of a wider set of earth system processes, and to sample changes at local scales. The methodology is necessarily dependent on a number of expert choices, which are highlighted throughout the paper.

Expression of estrogen receptor isoforms alpha and beta messenger RNA in vaginal tissue of premenopausal and postmenopausal women.

OBJECTIVE: To determine the messenger RNA expression patterns of estrogen receptor (ER)alpha and ER beta in human vaginal tissue. STUDY DESIGN: Reverse transcriptase-polymerase chain reaction was performed on tissue samples of 75 patients having anterior colporrhaphy (25 premenopausal, 25 postmenopausal receiving estrogen replacement therapy [ERT], 25 postmenopausal not receiving ERT). Levels of mRNA were normalized and ratios were calculated to assess relative levels of expression. RESULTS: All samples showed expression of the ER alpha isoform. Significant differences existed in ER alpha expression among the 3 cohorts (P =.023). Greater differences (P <.001) existed in ER beta expression. For both isoforms, the premenopausal group had the highest level, and the postmenopausal group receiving ERT had the lowest level. No significant difference in ER beta expression existed between postmenopausal groups. CONCLUSION: Significant differences exist between premenopausal and postmenopausal women in presence and expression of ER alpha and ER beta in vaginal tissue. Expression of ER beta markedly declines in menopause, regardless of ERT use.

Role of wide/radical hysterectomy and pelvic lymph node dissection in endometrial cancer with cervical involvement.

OBJECTIVE: The goal of this work was to assess retrospectively the role of wide/radical hysterectomy (RH) and pelvic lymph node dissection (LND) in endometrial cancer with cervical involvement. METHODS; From 1984 to 1993, 82 patients with endometrial cancer and cervical involvement were surgically managed at our institution. Of 57 patients with stage II (59%) or III (41%) disease receiving no preoperative therapy, 22 (39%) had simple hysterectomy (SH) and 35 (61%) had RH. Forty-four patients (77%) had pelvic LND, and 38 (67%) had adjuvant radiotherapy (RT). Median follow-up was 70 months. RESULTS: The 5-year disease-related survival (DRS) and recurrence-free survival (RFS) were 73 and 63%, respectively. Five-year DRS and RFS were 68 and 50%, respectively, in the SH group compared with 76% (P = 0.1) and 71% (P = 0.04) in the RH group. Distant recurrences occurred in 45% of patients with SH and in 23% with RH (P = 0.08). Local recurrence rates did not differ significantly. Considering only stage II tumors, we did not observe any recurrence among patients with negative nodes who had RH, irrespective of the administration of adjuvant RT. By contrast, adjuvant RT improved local control (even if not significantly) in stage II patients who had SH. Five-year DRS of stage III patients was 47%, but it was improved by adjuvant RT in the subgroup of patients who had RH. Independent variables associated with prognosis were stage III disease, deep myometrial invasion, RH, and adjuvant RT. CONCLUSION: RH and adjuvant RT appear to improve prognosis in endometrial cancer with cervical involvement. In particular, radical surgery alone is therapeutic in stage II patients with negative nodes, irrespective of the administration of RT. By contrast, RT can possibly improve local control in stage II patients who previously had SH. Overall, stage III patients have a poor prognosis that can be improved by a combination of radical surgery and adjuvant RT; however, associated therapy directed to extrapelvic sites is probably needed in patients with extrauterine disease.

Use of antihypertensive and antithrombotic medications after stroke in community-based care.

BACKGROUND: Secondary stroke prevention strategies include pharmacologic approaches to control hypertension and reduce thromboembolic risk. OBJECTIVE: To describe antithrombotic and antihypertensive medication use, and rates of blood pressure control in the Kansas City Stroke Study, a prospective stroke cohort receiving community-based care after primarily mild and moderate stroke. METHODS: Participants from 12 area hospitals provided information about medication use prior to stroke. Study personnel measured blood pressures at enrollment and at one, three, and six months, and collected medication data at six months during in-home assessment. RESULTS: Complete data at six months were available for 355 subjects with ischemic stroke, among whom 13% had atrial fibrillation and 67% had prior hypertension. Prior to stroke, only 45% of the patients were receiving any antithrombotic (anticoagulant and/or antiplatelet) therapy; this figure rose to 77% at six months. Antithrombotic treatment rates among those with atrial fibrillation were 59% before stroke and 83% at six months, including warfarin in 64%. Approximately 70% of subjects had controlled blood pressures one, three, and six months after stroke, defined as systolic blood pressure < or = 140 mm Hg and diastolic blood pressure < or = 90 mm Hg. Use of multiple antihypertensive agents was common; calcium-channel blockers and angiotensin-converting enzyme inhibitors were used most frequently. However, 19% of subjects with uncontrolled blood pressure were untreated at six months. CONCLUSIONS: Although room for improvement remains, these data suggest improved rates of antithrombotic and antihypertensive medication use after stroke in community-based care in a midwestern metropolitan community, compared with previous reports.

Surgery in ovarian cancer.

The role of surgery in the management of primary and recurrent ovarian cancer is reviewed. The data to support primary and secondary cytoreduction are summarized. The role of second-look surgery and of surgery in the palliation of ovarian cancer is also discussed.

Transitional cell carcinoma of the bladder mimicking recurrent paget's disease of the vulva: report of two cases, with one occurring in a myocutaneous flap.

BACKGROUND: Transitional cell carcinoma of the bladder may spread superficially along and beyond the urogenital epithelium, mimicking vulvar Paget's disease. CASES: These two cases illustrate unusual aspects of transitional cell carcinoma of the bladder and vulvar Paget's disease. Both patients had a history of breast cancer and previously had multiple operations for recurrent vulvar Paget's disease; one patient had a radical vulvectomy with transverse rectus abdominal muscle flap reconstruction. Both had a history of recurrent transitional cell carcinoma of the bladder. Both presented with recalcitrant transitional cell carcinoma of the bladder and clinically recurrent vulvar Paget's disease. Pathologic evaluation, however, revealed pagetoid spread of carcinoma in situ (CIS) throughout the urothelium, with an invasive component in the cervix and extension of the CIS into the rectum in one patient. CONCLUSION: If the history of the patient includes transitional cell carcinoma of the bladder and vulvar Paget's disease, histologic evaluation is needed for accurate diagnosis and proper treatment.

Mechanisms of female urinary continence under stress: frequency spectrum analysis.

Intravesical and urethral pressure signals during cough and Valsalva maneuvers for 15 continent women were analyzed with frequency spectrum analysis. Clear modulation of the urethral pressure changes by the intravesical pressure rise during stress maneuvers was demonstrated in the frequency bands of 14 and 7 Hz for cough and Valsalva, respectively. The linearity between the urethral and intravesical pressure signals was strong for cough, but relatively weaker for Valsalva. The observed linearity lead to the formulation of a modified continence equation to mathematically quantify stress leak point pressure (sLPP): sLPP=MUCP/(1-alpha1)+RBP. This algebraic equation demonstrated that sLPP depends on pressure transmission, resting bladder pressure, and maximum urethral closure pressure. The equation was validated with excellent theoretical predictions for the 15 continent subjects (R(2)=0.98 and 0.97 for cough and Valsalva leak point pressure, respectively) and good but somewhat weaker predictions for 46 stress incontinent women (R(2)=0.79 and 0.48, respectively). It has been shown that pressure transmission plays the most important role in female continence function, while it may be attributable to passive structural origin as evidenced by the minimal time delay between the two pressure signals, in the order of a few milliseconds. It can be concluded that coughing seems to have a more mechanical, rather than neuromuscular basis for its signal dynamics. This study suggests that a complete assessment of female stress continence function requires comprehensive urodynamic information in terms of pressure transmission, maximum urethral closure pressure, and resting bladder pressure.

Routes of lymphatic spread: a study of 112 consecutive patients with endometrial cancer.

OBJECTIVE: The goal of this work was to assess different patterns of lymphatic spread to pelvic and para-aortic lymph nodes (LNs) in endometrial cancer as a function of the location of tumor within the uterus. METHODS: Between 1984 and 1999, 625 patients with endometrial cancer were managed with hysterectomy and node dissection at our institution. The present study includes the 112 (18%) patients who had positive pelvic and/or para-aortic LNs; 41 (37%) of them had cervical involvement. RESULTS: The external iliac was the most commonly involved pelvic LN site both in patients with tumor limited to the corpus and in those with cervical invasion. Isolated pelvic LN metastases to a single site were more frequently observed in external iliac LNs and obturator LNs in patients with tumor confined to the uterine corpus, whereas they occurred more commonly in external iliac and common iliac LNs in patients with cervical involvement. Metastasis to the common iliac LNs was more frequent in patients with disease extension to the cervix. In fact, common iliac LNs were positive in 67% of patients with cervical invasion, compared with only 30% of those with tumor confined to the uterine corpus (P < 0.01). Para-aortic LN invasion was significantly associated with obturator LN status. In fact, para-aortic LNs were positive in 64% of patients with positive obturator LNs compared with 23% of patients with negative obturator LNs (P = 0.01). All patients with positive para-aortic LNs and tumor invading the cervix had positive common iliac LNs. By contrast, when tumor was limited to the corpus, common iliac LNs were involved in only 27% of patients with positive para-aortic LNs. CONCLUSION: External iliac LNs are the most commonly involved LNs in endometrial cancer. Compared with carcinomas limited to the uterine corpus, endometrial cancers invading the cervix spread more readily to the common iliac LNs. Furthermore, these data suggest that para-aortic LN metastases spread via a route shared by the common iliac LNs when tumor involves the cervix but spread predominantly via a route common to the obturator LNs (and/or external iliac LNs) when the primary tumor site is the corpus only.