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Well‐dated lacustrine records are essential to establish the timing and drivers of regional hydroclimate change. Searles Basin, California, records the depositional history of a fluctuating saline‐alkaline lake in the terminal basin of the Owens River system draining the eastern Sierra Nevada. Here, we establish a U‐Th chronology for the ∼76‐m‐long SLAPP‐SLRS17 core collected in 2017 based on dating of evaporite minerals. Ninety‐eight dated samples comprising nine different minerals were evaluated based on stratigraphic, mineralogic, textural, chemical, and reproducibility criteria. After the application of these criteria, a total of 37 dated samples remained as constraints for the age model. A lack of dateable minerals between 145 and 110 ka left the age model unconstrained over the penultimate glacial termination (Termination II). We thus established a tie point between plant wax δD values in the core and a nearby speleothem δ18O record at the beginning of the Last Interglacial. We construct a Bayesian age model allowing stratigraphy to inform sedimentation rate inflections. We find that the >210 ka SLAPP‐SRLS17 record contains five major units that correspond with prior work. The new dating is broadly consistent with previous efforts but provides more precise age estimates and enables a detailed evaluation of evaporite depositional history. We also offer a substantial revision of the age of the Bottom Mud‐Mixed Layer contact, shifting it from ∼130 ka to 178 ± 3 ka. The new U‐Th chronology documents the timing of mud and salt layers and lays the foundation for climate reconstructions. Plain Language Summary: Searles Lake, California, is currently a dry saltpan; however, in the past, it was a large and deep lake (>200 m). Lake levels have varied with changes in climate. These changes influenced the sediments deposited. Thus, changes in the lake sediments can be applied to understand the past environments of the region. Here, we developed a chronology for a 76‐m‐long sediment core using isotopic dating methods. The lake sediments contain many different minerals which can be dated. However, some of these minerals formed after the lake sediments were deposited and others have been chemically altered in the time since their formation. We developed criteria for the selection of samples that are the most likely to reflect the age of sediment deposition. We used the selected ages along with statistical modeling to determine the ages of the sediments with depth. We find that the core contains a record that spans over 200,000 years, including the last two glacial cycles. The age model presented here lays the foundation for the exploration of how past climate changes impacted water availability and vegetation in southeastern California. Key Points: >200 ka‐long sediment record of southwestern North American paleoenvironmentEstablishes general criteria for selection of evaporite minerals for U‐Th datingExplores a wide range of parameters for Bayesian age‐depth modeling [ABSTRACT FROM AUTHOR]

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To identify baseline patient characteristics (i.e., demographic and psychological factors, military background) associated with better posttraumatic stress disorder (PTSD) treatment retention among veterans, we conducted a systematic review. After an electronic database search for studies of PTSD treatment in veterans, two reviewers independently screened the literature for eligibility, abstracted study‐level information, and assessed risk of bias. As most studies used multivariate models to assess multiple potential predictors of retention simultaneously, the results were described narratively. The GRADE approach, adapted for prognostic literature, was used to assess the overall quality of evidence (QoE). In total, 19 studies reported in 25 publications met the inclusion criteria (n = 6 good quality, n = 9 fair quality, n = 4 poor quality). Definitions of treatment completion and dropout varied, and some studies lumped different therapy approaches together. Older age and higher treatment expectations were associated with better retention (moderate QoE). In 5 of 6 studies, baseline PTSD severity was not associated with retention, and the remaining study reported an association between better retention and more severe PTSD symptoms; the presence of more co‐occurring psychiatric disorders was associated with better retention (moderate QoE). QoE was low or insufficient to support conclusions for any other characteristics due to inconsistent results, imprecision, potential publication bias, possible study population overlap, study limitations, or lack of studies. More research is needed regarding the associations between modifiable factors (e.g., motivation, barriers, expectations) and retention, and consistent definitions of treatment completion and minimally adequate treatment should be adopted throughout the field. [ABSTRACT FROM AUTHOR]

Objectives: The prognostic value of kinetics of response to multiple myeloma (MM) therapy is controversial. We aimed to expand the knowledge on this topic by reviewing the kinetics of response to both first‐ and second‐line MM therapy, utilizing a homogeneously treated cohort and analyzing separately both M‐spike and light chain (LC) responses for each patient. Methods: We reviewed all patients who received first‐line cyclophosphamide, bortezomib and dexamethasone induction followed by autologous transplant with melphalan and lenalidomide maintenance in our center between 2007 and 2019. Results: Analyzing 360 patients, we observed no correlation between response kinetics to first‐ versus second‐line therapy at the individual patient level. Time to best response to first‐line therapy was not a predictor of outcome; however, longer time to best response was highly predictive of a favorable outcome in the second‐line setting, independent of other factors. Patients with IgA‐MM cleared their M‐spike faster than IgG‐MM, probably reflecting different half‐lives of these isotypes rather than disease biology, as the clearance of LC in both subtypes was similar. Conclusions: Analyzing both M‐spike and LC responses in a homogenously treated cohort, we identified important insights regarding the prognostic value of kinetic patterns. Prospective analysis may shed more light on unsolved questions. [ABSTRACT FROM AUTHOR]

Background: While Prostate Imaging Reporting and Data System (PI‐RADS) 4 and 5 lesions typically warrant prostate biopsy and PI‐RADS 1 and 2 lesions may be safely observed, PI‐RADS 3 lesions are equivocal. Purpose: To construct and cross‐validate a machine learning model based on radiomics features from T2‐weighted imaging (T2WI) of PI‐RADS 3 lesions to identify clinically significant prostate cancer (csPCa), that is, pathological Grade Group ≥ 2. Study type: Single‐center retrospective study. Population: A total of 240 patients were included (training cohort, n = 188, age range 43–82 years; test cohort, n = 52, age range 41–79 years). Eligibility criteria were 1) magnetic resonance imaging (MRI)‐targeted biopsy between 2015 and 2020; 2) PI‐RADS 3 index lesion identified on multiparametric MRI; (3) biopsy performed within 1 year of MRI. The percentages of csPCa lesions were 10.6% and 15.4% in the training and test cohorts, respectively. Field strength/sequence: A 3 T; T2WI turbo‐spin echo, diffusion‐weighted spin‐echo echo planar imaging, dynamic contrast‐enhanced MRI with time‐resolved T1‐weighted imaging. Assessment: Multislice volumes‐of‐interest (VOIs) were drawn in the PI‐RADS 3 index lesions on T2WI. A total of 107 radiomics features (first‐order histogram and second‐order texture) were extracted from the segmented lesions. Statistical Tests: A random forest classifier using the radiomics features as input was trained and validated for prediction of csPCa. The performance of the machine learning classifier, prostate specific antigen (PSA) density, and prostate volume for csPCa prediction was evaluated using receiver operating characteristic (ROC) analysis. Results: The trained random forest classifier constructed from the T2WI radiomics features good and statistically significant area‐under‐the‐curves (AUCs) of 0.76 (P = 0.022) for prediction of csPCa in the test set. Prostate volume and PSA density showed moderate and nonsignificant performance (AUC 0.62, P = 0.275 and 0.61, P = 0.348, respectively) for csPCa prediction in the test set. Conclusion: The machine learning classifier based on T2WI radiomic features demonstrated good performance for prediction of csPCa in PI‐RADS 3 lesions. Evidence Level: 4 Technical Efficacy: 2 [ABSTRACT FROM AUTHOR]

The phase 3 FIRST trial demonstrated significant improvement in progression‐free survival (PFS) and overall survival (OS) with an immune‐stimulatory agent, lenalidomide, in combination with low‐dose dexamethasone until disease progression (Rd continuous) vs melphalan +prednisone + thalidomide (MPT) in transplant‐ineligible patients with newly diagnosed multiple myeloma (NDMM). Rd continuous similarly extended PFS vs fixed‐duration Rd for 18 cycles (Rd18). Outcomes in the Canadian/US subgroup (104 patients per arm) are reported in this analysis. Rd continuous demonstrated a significant improvement in PFS vs MPT (median, 29.3 vs 20.2 months; HR, 0.69 [95% CI, 0.49‐0.97]; p = 0.03326) and an improvement vs Rd18 (median, 21.9 months). Median OS was 56.9 vs 46.8 months with Rd continuous vs MPT (p = 0.15346) and 59.5 months with Rd18. The overall response rate was higher with Rd continuous and Rd18 (78.8% and 79.8%) vs MPT (65.4%). In the 49.0%, 52.9%, and 29.8% of patients with at least very good partial response in the Rd continuous, Rd18, and MPT arms, respectively, the median PFS was 56.0, 30.9, and 40.2 months, respectively. The most common grade 3/4 treatment‐emergent adverse events were neutropenia (28.4%, 30.1%, and 52.0%), anemia (23.5%, 21.4%, and 23.5%), and infections (37.3%, 30.1%, and 24.5%) with Rd continuous, Rd18, and MPT, respectively. These results were consistent with those in the intent‐to‐treat population, confirming the benefit of Rd continuous vs MPT in the Canadian/US subgroup and supporting the role of Rd continuous as a standard of care for transplant‐ineligible patients with NDMM. [ABSTRACT FROM AUTHOR]

Premise: Plant biodiversity is threatened, yet many species remain undescribed. It is estimated that >50% of undescribed species have already been collected and are awaiting discovery in herbaria. Robust automatic species identification algorithms using machine learning could accelerate species discovery. Methods: To encourage the development of an automatic species identification algorithm, we submitted our Herbarium 2019 data set to the Fine‐Grained Visual Categorization sub‐competition (FGVC6) hosted on the Kaggle platform. We chose to focus on the flowering plant family Melastomataceae because we have a large collection of imaged herbarium specimens (46,469 specimens representing 683 species) and taxonomic expertise in the family. As is common for herbarium collections, some species in this data set are represented by few specimens and others by many. Results: In less than three months, the FGVC6 Herbarium 2019 Challenge drew 22 teams who entered 254 models for Melastomataceae species identification. The four best algorithms identified species with >88% accuracy. Discussion: The FGVC competitions provide a unique opportunity for computer vision and machine learning experts to address difficult species‐recognition problems. The Herbarium 2019 Challenge brought together a novel combination of collections resources, taxonomic expertise, and collaboration between botanists and computer scientists. [ABSTRACT FROM AUTHOR]

Objective: Obesity is preventable and yet continues to be a major risk factor for chronic disease. Multiple prevention approaches have been proposed across multiple settings where people live, work, learn, worship, and play. This review searched the vast literature on obesity prevention interventions to assess their effects on daily energy consumed and energy expended.Methods: This systematic review (PROSPERO registration CRD42017077083) searched seven databases for systematic reviews and studies reporting energy intake and expenditure. Two independent reviewers screened 5,977 citations; data abstraction supported an evidence map, comprehensive evidence tables, and meta-analysis; critical appraisal assessed risk of bias; and the quality of evidence was evaluated using Grading of Recommendations Assessment, Development and Evaluation (GRADE).Results: Hundreds of published reviews were identified. However, few studies reported on energy intake and expenditure to determine intervention success. Ninety-nine studies across all intervention domains were identified. Few areas demonstrated statistically significant effects across studies; school-based approaches and health care initiatives reduced energy consumed, education reduced energy consumed and increased energy expended, and social-group approaches increased energy expenditure.Conclusions: Despite the amount of research on obesity prevention interventions, very few studies have provided relevant information on energy intake and expenditure, two factors determining weight gain. Future research needs to fill this gap to identify successful public health policies. [ABSTRACT FROM AUTHOR]

The article presents a case study of a 12-year-old girl who was referred to a tertiary paediatric centre due to developed intermittent fevers and diagnoses revealed subacute bacterial endocarditis, occult osteomyelitis, cat scratch fever and rickettsial disease after series of examinations.

We report the use of isolable primary and secondary alkylcarbastannatrane nucleophiles in site-specific fluorination reactions. These reactions occur without the need for transition metal catalysis or in situ activation of the nucleophile. In the absence of the carbastannatrane backbone, alkyltin nucleophiles exhibit no activity towards fluorination. When enantioenriched alkylcarbastannatranes are employed, fluorination occurs predominately via a stereoinvertive mechanism to generate highly enantioenriched alkyl fluoride compounds. These conditions can also be extended to stereospecific chlorination, bromination, and iodination reactions. [ABSTRACT FROM AUTHOR]

Objectives Heavily pretreated patients with relapsed and refractory multiple myeloma are susceptible to treatment-related adverse events (AEs). Managing AEs are important to ensure patients continue therapy long enough to receive the best clinical benefit. Data from the MM-002, MM-003, and MM-010 trials were pooled to further characterize the safety profile of pomalidomide plus low-dose dexamethasone and AE management. Methods This analysis included 1088 patients who received ≥ 2 prior therapies, including lenalidomide and bortezomib, and progressed ≤ 60 days of last therapy. Patients received 28-day cycles of pomalidomide 4 mg/day on days 1-21 and low-dose dexamethasone 40 mg (20 mg if aged > 75 years) weekly until disease progression or unacceptable toxicity. Thromboprophylaxis was required. Results The most common grade 3/4 AEs were neutropenia (56.2%), anemia (32.3%), and thrombocytopenia (25.8%), which occurred within the first few cycles of treatment. Grade 3/4 infections occurred in 33.7% patients, of whom 13.9% had pneumonia, and 40.3% had neutropenia. Pomalidomide dose reductions or interruptions were reported in 24.2% and 66.0% of patients, respectively. AEs were managed by dose modifications and/or supportive care. Conclusions Pomalidomide plus low-dose dexamethasone showed an acceptable safety profile, and AEs were well managed according to study protocols and established guidelines. [ABSTRACT FROM AUTHOR]

Lenalidomide in combination with dexamethasone (Len-dex) represents a highly effective treatment in relapsed/refractory multiple myeloma ( RRMM) patients. However, an increased risk of secondary primary malignancies ( SPMs), including myelodysplastic syndrome ( MDS) and acute myelogenous leukemia ( AML) has been described in patients receiving lenalidomide. In order to assess the incidence and features of this complication, we reviewed 195 patients with RRMM treated with Len-dex at our institution. The median follow-up time from diagnosis of MM was 73 months (10-234 months) and from initiation of Len-dex was 19 months (1-104 months). The median duration of Len-dex for all patients was 7.8 months (range 1-90 months). The incidence rate ( IR) for all SPMs from start of Len-dex was 2.37 per 100 patient-years, which reflected an IR of 1.29 for MDS/ AML and 1.08 for nonhematologic malignancies ( NHM). MDS was the most common SPM noted. The cumulative IR of SPM at 5 years was 1.54% from the time of MM diagnosis and 5.24% from starting Len-dex. Multivariable cumulative incidence of SPM analysis identified older age ( P = 0.005) and prior number of regimens ( P = 0.026) as adverse risk factors. We found more concomitant G- CSF use ( P = 0.029) in patients with MDS/ AML, however, causal association is not clear. The progression-free survival after Len-dex was the longest for patients in MDS/ AML group, and the 5-year overall survival did not differ among groups. Although the rate of SPM was relatively low with Len-dex, concomitant G- CSF should be used judiciously and patients receiving this regimen should be observed for the development of this complication. [ABSTRACT FROM AUTHOR]

The article presents a case study of a 46-year-old female with posterior sub capsular cataracts (PSCC) who was treated with Nd: YAG laser vitreolysis for floaters treatment earlier. It notes Nd:YAG laser vitreolysis caused cataract formation with posterior capsule defects in the patient. The article discusses side effect of the Nd:YAG laser treatment for cataract including cause retinal holes, vitreous hemorrhage, chorioretinal bleeding and elevated intraocular pressure.

Purpose There have been only a limited number of studies examining the accommodative response that occurs when the two eyes are provided with disparate accommodative stimuli, and the results from these studies to date have been equivocal. In this study, we therefore aimed to examine the capacity of the visual system to aniso-accommodate by objectively measuring the interocular difference in the accommodation response between fellow dominant and non-dominant eyes under controlled monocular and binocular viewing conditions during short-term exposure to aniso-accommodative stimuli. Methods The accommodative response of each eye of 16 young isometropic adults (mean age 22 ± 2 years) with normal binocular vision was measured using an open-field autorefractor during a range of testing conditions; monocularly (accommodative demands ranging from 1.32 to 4.55 D) and binocularly while altering the accommodation demand for each eye (aniso-accommodative stimuli ranging from 0.24 to 2.05 D). Results Under monocular viewing conditions, the dominant and non-dominant eyes displayed a highly symmetric accommodative response; mean interocular difference in spherical equivalent 0.01 ± 0.06 D (relative) and 0.22 ± 0.06 D (absolute) ( p > 0.05). During binocular viewing, the dominant eye displayed a greater accommodative response (0.11 ± 0.34 D relative and 0.24 ± 0.26 D absolute) irrespective of whether the demand of the dominant or non-dominant eye was altered ( p = 0.01). Astigmatic power vectors J0 and J45 did not vary between eyes or with increasing accommodation demands under monocular or binocular viewing conditions ( p > 0.05). Conclusion The dominant and non-dominant eyes of young isometropic individuals display a similar consensual lag of accommodation under both monocular and binocular viewing conditions, with the dominant eye showing a small but significantly greater (by 0.12-0.25 D) accommodative response. Evidence of short-term aniso-accommodation in response to asymmetric accommodation demands was not observed. [ABSTRACT FROM AUTHOR]

Venous thromboembolism ( VTE) has an increased incidence in patients with multiple myeloma ( MM), especially during chemotherapy. Mechanisms including upregulation of procoagulant factors, such as factor VIII, have been postulated. The National Cancer Institute of Canada Clinical Trials Group MY.10 phase III clinical trial compared thalidomide-prednisone to observation for 332 patients with MM post-autologous stem cell transplantation ( ASCT), with a primary endpoint of overall survival and various secondary endpoints including the incidence of VTE. One hundred and fifty-three patients had biomarker data, including D-dimer, factor VIII and thrombin anti-thrombin ( TAT) levels collected post- ASCT at baseline and 2 months after intervention investigating in-vivo thrombin generation. Differences between the time-points included a significant reduction over time in D-dimer, factor VIII and TAT levels in the observation group and sustained elevation of D-dimer, significant increase in factor VIII and reduction in TAT levels in the thalidomide-prednisone group. Eight VTE events were reported in this subset of study patients, all in the thalidomide-prednisone arm, with a trend to increase in D-dimer levels over time in those patients with VTE. This study provides physiological and clinical evidence for an increased risk of VTE associated with thalidomide-prednisone maintenance therapy post- ASCT for MM. [ABSTRACT FROM AUTHOR]

This single institution, open label Phase I- II dose escalation trial evaluated the safety and efficacy of the combination of lenalidomide (Revlimid®), cyclophosphamide and prednisone ( CPR) in patients with relapsed/refractory multiple myeloma. The maximal administered dose of CPR consisted of cyclophosphamide 300 mg/m2 on day 1, 8, and 15, lenalidomide 25 mg on d 1-21 and prednisone 100 mg every other day in a 28-d cycle. Between November 2007 and June 2009, 32 patients were entered in cohorts of three at three dose levels. The median age was 64 years, 59% were male, with a median two prior regimens. Responding patients could stay on treatment until progression. The full-dose CPR regimen produced no dose-limiting toxicity and was delivered for a median of 16 months (3·5-65 months) with acceptable safety and tolerance. The overall response rate (≥ partial response) was 94% at a median follow up of 28 months. The median progression-free survival was 16·1 months [95% confidence interval ( CI); 10·9-22·5 months], while the median overall survival was 27·6 months (95% CI; 16·8-36·6 months). Only the beta-2 microglobulin level at protocol entry correlated with a better survival ( P = 0·047). These observations compare favourably with other 2- and 3- drug combinations for relapsed/refractory myeloma, and suggest that CPR should be evaluated further in the setting of relapsed/refractory disease, or in newly diagnosed patients. [ABSTRACT FROM AUTHOR]

Autologous stem-cell transplant has been widely used to treat patients with AL amyloidosis. However, transplant-related mortality rates are high, and a recent randomized trial suggested that non-transplant regimens produced comparable results with less toxicity. In order to define the role of patient selection in stem cell transplantation, we evaluated 78 consecutive AL amyloidosis patients transplanted at our centre. Transplant-related mortality occurred in 11·5%. Complete haematological response and organ response were achieved in 56% and 60%. Median overall survival was significantly lower for patients with brain-type natriuretic peptide ( BNP) >300 pg/ml (17·5 months vs. not-reached) ( P = 0·0004), troponin-I >0·07 ng/ml (13·5 months vs. not-reached) ( P = 0·00001) and those not achieving a complete haematological response (88 months vs. not-reached) ( P = 0·0345); high BNP and troponin-I were the most important predictive factors in a multivariate analysis. Based on this study, patients with BNP <300 pg/ml and/or normal levels of troponin-I should be considered transplant candidates. [ABSTRACT FROM AUTHOR]

Involvement of the central nervous system ( CNS) in multiple myeloma ( MM) is a rare complication, with reported survival of <6 months. This report describes 37 MM patients with leptomeningeal and/or parenchymal brain involvement treated at our institution and identifies factors associated with long-term survival. From January 1999 to December 2010, 37 patients with CNS MM were evaluated at our institution. Clinical characteristics, treatment and survival were retrospectively collected. CNS disease was present at MM diagnosis in 24% and at relapse in 76%. Plasma cell leukemia (40%) and skull plasmacytomas (65%) were common, suggesting haematological and contiguous spread. Intrathecal ( IT) chemotherapy was used in 81%, cranial and/or spinal irradiation in 78%, and various systemic therapies [immunomodulatory agents ( IMiDs) (51%), cisplatin-based ( DPACE; cisplatin, doxorubicin, cyclophosphamide, etoposide) (27%), bortezomib (19%), alkylators (11%), dexamethasone alone (8%), auto-transplant (5%)]. Median survival from CNS disease was only 4·6 months [95% confidence interval ( CI): 2·8-6·7]; however, nine patients had prolonged survival (median: 17·1 months, 95% CI: 13·2-67·4). In general, these long-term survivors were treated with radiotherapy, multi-dosing IT chemotherapy, and IMi D-containing therapy. CNS MM is a highly aggressive disease but in our experience, long-term survival can be achieved with the combination of multi-dosing IT chemotherapy, radiation and IMi D-based therapy. [ABSTRACT FROM AUTHOR]

Dexamethasone ± thalidomide with infusion of cisplatin, doxorubicin, cyclophosphamide, and etoposide [D(T) PACE] is generally reserved as salvage therapy for aggressive multiple myeloma ( MM) or plasma cell leukaemia ( PCL) resistant to conventional therapies. The efficacy and durability of this potentially toxic regimen in this setting is unclear. We identified 75 patients who received D(T) PACE for relapsed/refractory MM at two tertiary care centres: Princess Margaret Hospital, Toronto and Mayo Clinic Arizona. At time of D(T) PACE, 16 patients had PCL and three patients had leptomeningeal disease. Patients were heavily pretreated (median three prior regimens, range 1-12; prior autologous stem cell transplant [ ASCT] 33%). Overall response rate was 49% (very-good partial response 16%, partial response 33%) with stable disease in an additional 36%. Median progression-free survival ( PFS) was 5·5 months (95% confidence interval [ CI]:4·3-9·8); overall survival ( OS) 14·0 months (95% CI:8·7-19·3). Thirty-five patients proceeded to ASCT or clinical trial, with median PFS for this subset of 13·4 months (95% CI:7·7-20·1) and OS 20·5 months (95% CI:14·8-63·8). D(T) PACE is an effective salvage therapy for heavily pretreated MM patients. Although the overall response rate of 49% in this poor prognosis cohort is reasonable, the PFS is short, suggesting the best role for D(T) PACE is in bridging to definitive therapy, such as transplantation. [ABSTRACT FROM AUTHOR]

Chinese American pregnant women and women of childbearing age face economic, cultural and linguistic barriers in accessing mainstream health care services. The Charles B. Wang Community Health Center developed a culturally and linguistically competent genetic education workshop for high-risk Chinese American prenatal patients. Patients referred for genetic counseling for thalassemia, abnormal triple screen results, and/or advanced maternal age were recruited to participate in the workshop. The workshop provided basic 'genetic 101' education, focusing on topics that were directly relevant to the patients' reasons for referral. The effectiveness of the workshop was measured using a quasi-experimental design with pre-post surveys administered to intervention and control group participants. The evaluation also included a genetic counselor assessment and a pilot study of genetic counseling appointment length. Overall, workshop participants showed significant increases in knowledge, positive attitude and self-efficacy regarding genetic services as compared to their control group counterparts. The pilot appointment length study data revealed that the workshop reduced the length of the genetic counseling appointment time by 40%. These positive findings suggest that it would be worthwhile to replicate the genetic education workshop at other health agencies serving Chinese-speaking populations and that further evaluation research should be conducted. [ABSTRACT FROM AUTHOR]

A correction to the article "The short-term accommodation response to aniso-accommodative stimuli in isometropia," by Stephen J. Vincent, Michael J. Collins, and Scott A. Read in a previous issue is presented.

Lenalidomide gained Food and Drug Administration (FDA) approval for treatment of patients with relapsed or refractory multiple myeloma (MM) in combination with dexamethasone in June 2006. In April 2005, the FDA and patient advocacy groups requested an expanded access programme to both provide lenalidomide to patients likely to benefit and obtain additional safety information. Relapsed/refractory MM patients received lenalidomide 25 mg/d (days 1–21) and dexamethasone 40 mg/d (days 1–4, 9–12, and 17–20 of cycles 1–4; days 1–4 only from cycle 5 onwards), in 4-week cycles until disease progression, study drug discontinuation, or lenalidomide approval. Of the 1438 patients enrolled, ∼60% were male, median age was 64 years, and 61·7% had Durie-Salmon stage III disease. Median time on study was 15·4 weeks (range: 0·1–49·1) and median dose was 25 mg. The most common adverse events (AEs) were haematological (49%), gastrointestinal (59%), and fatigue (55%). The most common grade ≥3 AEs were haematological (45%), fatigue (10%), and pneumonia (7%). The most common serious AEs were pneumonia (8%), pyrexia (4%), and deep-vein thrombosis (3%). Primary cause of death was disease progression (10%). Safety data confirmed known AEs of lenalidomide plus dexamethasone therapy in patients with relapsed/refractory MM. [ABSTRACT FROM AUTHOR]

Objective: Tryptophan hydroxylase is the rate-limiting enzyme in the synthesis of serotonin, and thus its gene, TPH, has been extensively studied as a risk factor for both bipolar disorder and major depressive disorder. The purpose of the present report is to synthesize the available data on these putative associations and derive best estimates of the nature and magnitude of the influence of TPH on risk for mood disorders. Methods: We identified studies that examined the TPH A218C polymorphism in relation to major depressive disorder or bipolar disorder using the PubMed online search engine, ultimately including 10 case-control studies in two meta-analyses. Results: The AA genotype had a significant effect on risk for bipolar disorder in comparison to either the CC or AC genotypes, suggesting that the A allele may increase risk for bipolar disorder in a recessive manner. None of the three genotypes significantly increased risk for major depressive disorder relative to any of the other genotypes. Conclusion: The homozygous recessive genotype of the TPH A218C polymorphism has a significant effect on risk for bipolar disorder but not major depressive disorder. A possible explanation for these results is that the A allele influences mood by permitting or facilitating mania while having no effect on depression. Further replication of these findings in additional large case-control and family-based association is needed before TPH can be designated a risk gene for bipolar disorder. [ABSTRACT FROM AUTHOR]

The frequency and prognostic relevance of translocations t(11;14) and t(4;14), the most common translocations involving the immunoglobulin heavy chain (IgH) gene in multiple myeloma (MM), were investigated in 128 patients treated with intensive chemotherapy and autologous stem cell transplant. Myeloma cells were identified by cytoplasmic light chain immunofluorescence combined with fluorescence in situ hybridization (cIg-FISH) for detection of translocations t(11;14) and t(4;14). Overall, t(11;14) was detected in 16 of 125 (12·8%) and t(4;14) in 15 of 120 (12·5%) patients. Progression-free and overall survivals were similar for patients with or without t(11;14). However, patients with t(4;14) had significantly shorter progression-free (median 9·9 months vs. 25·8 months; P = 0·0003) and overall survivals (median 18·3 months vs. 48·1 months; P < 0·0001) than patients without t(4;14). The t(4;14) was associated with IgA and t(11;14) with light chain MM. There was no association between the t(11;14) or t(4;14) and other biological parameters including age, gender, haemoglobin, β-2 microglobulin, C-reactive protein, calcium, creatinine, albumin, or the percentage of bone marrow plasma cells. Multivariate analysis identified t(4;14) as the only adverse prognostic factor for both progression-free survival and overall survival. Our results indicate that the t(4;14) detected by cIg-FISH is associated with a poor prognosis in MM patients receiving intensive chemotherapy and autotransplant. [ABSTRACT FROM AUTHOR]

Histological transformation from a follicular non-Hodgkin's lymphoma (NHL) to a higher grade lymphoma carries a poor prognosis despite treatment with aggressive anthracycline-based chemotherapy. We retrospectively analysed 35 patients with histologically transformed NHL who underwent high-dose therapy and autotransplantation at our centre. Patients up to 65 years old were eligible for autotransplant at the time of transformation or with subsequent relapses, provided that chemosensitivity to a salvage regimen could be demonstrated. All patients received high-dose therapy [etoposide 60 mg/kg, melphalan 160 mg/m2 and fractionated total body irradiation (TBI) 12 Gy] followed by unpurged autologous bone marrow or blood stem cell rescue. Most patients (69%) had advanced stage disease (stages 3–4) at transformation and bone marrow involvement was common (49%). Twenty-six (74%) patients were in partial remission (PR) and nine (26%) in complete remission (CR) at the time of transplant. Median duration from transformation to transplant was 10·9 months (range, 5·2 months-4·6 years). At a median follow up of 52 months after autotransplant, 19 (54%) patients had died. Causes of death were progressive lymphoma in nine patients (26%), treatment-related mortality (TRM) in seven (20%) and myelodysplasia in three (8%). Only five patients in our cohort were > 60 years old, but all died as a result of treatment-related causes (mostly pulmonary infections). Five-year overall survival and progression-free survival from time of transplant were 37% and 36% respectively. Using multivariate analysis of factors including gender, age, stage, extranodal disease, disease bulk, B symptoms, number of prior therapies, relapse status and CR/PR status at transplant, only advanced age significantly predicted for survival from autotransplant (P = 0·002). Our survival data are comparable to previous reports of autotransplantation for transformed NHL and suggest a benefit over standard chemotherapy alone in selected patients. However, our high TRM cautions the use of aggressive therapy, including TBI, in patients over 60 years old. [ABSTRACT FROM AUTHOR]

The article presents a study on cyclophosphamide, bortezomib and dexamethasone induction therapy for newly diagnosed patients with multiple myeloma (MM). It discusses the development of new therapies for MM, method used to calculate the patients' survival, and the overall response for all patients in the study.

In normal platelet α-granules von Willebrand factor (VWF) is stored with multimerin and factor V in an eccentric electron-lucent zone. Because the platelet stores of VWF are deficient in ‘platelet low’ type 1 and type 3 von Willebrand disease (VWD), we investigated their electron-lucent zone proteins. The patients with VWD had partial to complete deficiencies of plasma and platelet VWF but normal α-granular multimerin and factor V, and normal α-granular fibrinogen, thrombospondin-1, fibronectin, osteonectin and P-selectin. In type 3 VWD platelets, α-granular electron-lucent zones lacking VWF-associated tubules were identified and multimerin was found in its normal α-granular location. These findings indicate that the formation of the electron-lucent zone and the sorting of multimerin to this region occur independent of VWF. The isolated abnormalities in VWF suggests a VWF gene mutation is the cause of ‘platelet low’ type 1 VWD. [ABSTRACT FROM AUTHOR]

The article presents the result of a study which examined the use of single agent lenalidomide in the treatment of chronic lymphocytic leukemia (CLL). The researchers concluded that there is no correlation between long-term use of lenaidomide and cumulative toxicities such as myelosuppression, opportunistic infections and infections of the upper respiratory tract and skin. Other studies on the moderate efficacy of lenalidomide and cereblon (CRBN) are cited.

We report a single case study of concordant bilateral Duane’s Retraction Syndrome (DRS) (type 1) in female monozygotic (MZ) twins aged 47 years. The twin pair were recruited through the Australian Twin Registry as part of a twin study on myopia. This twin pair were full term and had a similar birth weight: 2.27 kg and 1.81 kg in twin 1 and twin 2, respectively. There was no report of any other childhood medical conditions in either twin. Both twins had an equal amount of restriction in right and left abduction. Narrowing of the palpebral fissures and globe retraction in right and left adduction was also observed in both twins. To our knowledge this is the first case to report concordant bilateral DRS (type 1) in female MZ twins. The concordance for the presence of DRS and associated clinical signs observed in this MZ twin pair supports a genetic origin to DRS. [ABSTRACT FROM AUTHOR]

Female monozygotic twins aged 54 years discordant for myopia are reported. One twin presented with bilateral high myopia (right eye = −6.00/+0.50 × 5°, left eye = −6.00/+0.50 × 45°) and her identical twin had no significant refractive error (right eye = −0.50/plano, left eye = −0.50/+0.75 × 40°). An explanation for the striking refractive discordance seen in this case report is yet to be determined. [ABSTRACT FROM AUTHOR]

The article reviews the web site of medical education, located at www.mja.com.au, of central retinal venous pulsations video.