Banff 2022 pancreas transplantation multidisciplinary report: Refinement of guidelines for T cell-mediated rejection, antibody-mediated rejection and islet pathology. Assessment of duodenal cuff biopsies and noninvasive diagnostic methods.

The Banff pancreas working schema for diagnosis and grading of rejection is widely used for treatment guidance and risk stratification in centers that perform pancreas allograft biopsies. Since the last update, various studies have provided additional insight regarding the application of the schema and enhanced our understanding of additional clinicopathologic entities. This update aims to clarify terminology and lesion description for T cell-mediated and antibody-mediated allograft rejections, in both active and chronic forms. In addition, morphologic and immunohistochemical tools are described to help distinguish rejection from nonrejection pathologies. For the first time, a clinicopathologic approach to islet pathology in the early and late posttransplant periods is discussed. This update also includes a discussion and recommendations on the utilization of endoscopic duodenal donor cuff biopsies as surrogates for pancreas biopsies in various clinical settings. Finally, an analysis and recommendations on the use of donor-derived cell-free DNA for monitoring pancreas graft recipients are provided. This multidisciplinary effort assesses the current role of pancreas allograft biopsies and offers practical guidelines that can be helpful to pancreas transplant practitioners as well as experienced pathologists and pathologists in training.

Focal segmental glomerulosclerosis and proteinuria associated with Myo1E mutations: novel variants and histological phenotype analysis.

BACKGROUND: Pathogenic mutations in the non-muscle single-headed myosin, myosin 1E (Myo1e), are a rare cause of pediatric focal segmental glomerulosclerosis (FSGS). These mutations are biallelic, to date only reported as homozygous variants in consanguineous families. Myo1e regulates the actin cytoskeleton dynamics and cell adhesion, which are especially important for podocyte functions. METHODS: DNA and RNA sequencing were used to identify novel MYO1E variants associated with FSGS. We studied the effects of these variants on the localization of Myo1e in kidney sections. We then analyzed the clinical and histological observations of all known pathogenic MYO1E variants. RESULTS: We identified a patient compound heterozygote for two novel variants in MYO1E and a patient homozygous for a deletion of exon 19. Computer modeling predicted these variants to be disruptive. In both patients, Myo1e was mislocalized. As a rule, pathogenic MYO1E variants map to the Myo1e motor and neck domain and are most often associated with steroid-resistant nephrotic syndrome in children 1-11 years of age, leading to kidney failure in 4-10 years in a subset of patients. The ultrastructural features are the podocyte damage and striking diffuse and global Alport-like glomerular basement membrane (GBM) abnormalities. CONCLUSIONS: We hypothesize that MYO1E mutations lead to disruption of the function of podocyte contractile actin cables resulting in abnormalities of the podocytes and the GBM and dysfunction of the glomerular filtration barrier. The characteristic clinicopathological data can help to tentatively differentiate this condition from other genetic podocytopathies and Alport syndrome until genetic testing is done. A higher resolution version of the Graphical abstract is available as Supplementary information.

Clear cell papillary renal cell carcinoma in a transplant kidney.

Large renal cell carcinomas (RCC) arising in allograft kidney transplants are rarely encountered. The distinct RCC sub-type, clear cell papillary RCC (CP-RCC), has mostly been described in non-immunosuppressed patients. Here we report the presentation, management and pathologic diagnosis of a large (11.2 cm, pT2b), multifocal, CP-RCC in a poorly functioning renal allograft of a 63-year-old woman 19 years following kidney transplant. Preoperative angiographic kidney embolization was successfully performed prior to allograft nephrectomy, with an excellent surgical, oncologic and clinical outcome.

C4d-expressing glomerulopathy and proteinuria post transplantation of a too-big-for-size mismatched kidney allograft: An unusual case with good outcome
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A 5-year-old severely growth-retarded child with tubulointerstitial, oliguric end-stage renal disease received an adult-size kidney transplant. Three years post grafting under standard triple immunosuppression (mycophenolate mofetil, tacrolimus, and prednisone) de novo nephrotic range proteinuria without the nephrotic syndrome developed. Graft function was normal (serum creatinine: 0.2 - 0.3 mg/dL), there were no donor-specific HLA antibodies (DSA), and the urine sediment was inactive. Two biopsies collected 3 and 4 years post-transplantation showed severe glomerular capillary wall remodeling and associated pseudolinear C4d staining as morphologic correlates for the proteinuria. Changes resembled those seen in so-called "size-mismatch transplant glomerulopathies". There was no evidence of a glomerulonephritis, acute or chronic rejection including transplant glomerulopathy, interstitial fibrosis, peritubular capillary C4d deposits, or multilamination of peritubular capillary basement membranes. The glomerular changes were not detected in the implantation zero-hour biopsy or the recipient's native renal biopsy. At the end of follow-up 64 months post transplantation, proteinuria persisted at subnephrotic levels in the setting of stable graft function and undetectable DSAs. This unique case adds to the list of causes of nonrejection-associated post-transplant proteinuria. It demonstrates for the first time that a too-large-for-body-size mismatched graft is associated with a presumably sheer stress-induced C4d expressing glomerulopathy, severe proteinuria, and favorable outcome.
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The END network couples spindle pole assembly to inhibition of the anaphase-promoting complex/cyclosome in early mitosis.

Cyclin-dependent kinase 1 (Cdk1) initiates mitosis and later activates the anaphase-promoting complex/cyclosome (APC/C) to destroy cyclins. Kinetochore-derived checkpoint signaling delays APC/C-dependent cyclin B destruction, and checkpoint-independent mechanisms cooperate to limit APC/C activity when kinetochores lack checkpoint components in early mitosis. The APC/C and cyclin B localize to the spindle and poles, but the significance and regulation of these populations remain unclear. Here we describe a critical spindle pole-associated mechanism, called the END (Emi1/NuMA/dynein-dynactin) network, that spatially restricts APC/C activity in early mitosis. The APC/C inhibitor Emi1 binds the spindle-organizing NuMA/dynein-dynactin complex to anchor and inhibit the APC/C at spindle poles, and thereby limits destruction of spindle-associated cyclin B. Cyclin B/Cdk1 activity recruits the END network and establishes a positive feedback loop to stabilize spindle-associated cyclin B critical for spindle assembly. The organization of the APC/C on the spindle also provides a framework for understanding microtubule-dependent organization of protein destruction.

Calmodulin-dependent protein kinase II activation promotes kidney mesangial expansion in streptozotocin-induced diabetic mice.

Calcium-calmodulin-dependent protein kinase II (CaMKII) is upregulated in diabetes mellitus (DM), leading to the overproduction of collagen in the myocardium. We hypothesized that CaMKII plays a role in the development of diabetic nephropathy (DN). Streptozotocin (STZ) injection into FVB wild-type mice led to mild mesangial matrix expansion, reproducing an essential feature of early human DN. Mesangial matrix measurements were performed on trichrome-stained paraffin sections using a trainable segmentation method based on WEKA (Waikato Environment for Knowledge Analysis) Image J-Fiji plugin (TWS plugin), and the electron micrographs of the whole glomeruli stitched from individual 4800x partial glomerular images. Both methods demonstrated that the statistically significant mesangial matrix expansion seen in the diabetic mice was prevented by chronic pretreatment with KN-93, a small molecule CaMKII inhibitor. This study indicates a role for CaMKII in the development of mesangial alterations in diabetes and suggests a possible new therapeutic target.

The G2 p38-mediated stress-activated checkpoint pathway becomes attenuated in transformed cells.

When human cells are stressed during G2, they are delayed from entering mitosis via a checkpoint mediated by the p38 kinase, and this delay can be modeled by the selective activation of p38 with anisomycin. Here, we report, on the basis of live-cell studies, that 75 nM anisomycin transiently (1 hr) activates p38 which, in turn, rapidly and completely blocks entry into mitosis for at least 4 hr in all primary, telomerase- or spontaneously immortalized (p53+ and pRB+) human cells. However, the same treatment does not delay entry into mitosis in cancer cells, or the delay in entering mitosis is shortened, even though it induces a similar transient and comparable (or stronger) activation of p38. Because the primary substrate of p38, the MK2 kinase, is also transiently (1-2 hr) activated by anisomycin in both normal and cancer cells, checkpoint disruption in transformed cells occurs downstream of MK2. Finally, observations on isogenic lines reveal that the duration of the stress checkpoint is shortened in cells lacking both p53 and pRb and that the constitutive expression of an active H-Ras oncogene in these cells further attenuates the checkpoint via an ERK1/2-dependent manner. Thus, transformation leads to attenuation of the p38-mediated stress checkpoint. This outcome is likely selected for during transformation because it confers the ability to outgrow normal cells under stressful in vitro (culture) or in vivo (tumor) environments. Our data caution against using cancer cells to study how p38 produces a G2 arrest.

The small organic compound HMN-176 delays satisfaction of the spindle assembly checkpoint by inhibiting centrosome-dependent microtubule nucleation.

HMN-176 is a potential new cancer therapeutic known to retard the proliferation of tumor cell lines. Here, we show that this compound inhibits meiotic spindle assembly in surf clam oocytes and delays satisfaction of the spindle assembly checkpoint in human somatic cells by inducing the formation of short and/or multipolar spindles. HMN-176 does not affect centrosome assembly, nuclear envelope breakdown, or other aspects of meiotic or mitotic progression, nor does it affect the kinetics of Spisula or mammalian microtubule (MT) assembly in vitro. Notably, HMN-176 inhibits the formation of centrosome-nucleated MTs (i.e., asters) in Spisula oocytes and oocyte extracts, as well as from isolated Spisula or mammalian centrosomes in vitro. Together, these results reveal that HMN-176 is a first-in-class anticentrosome drug that inhibits proliferation, at least in part, by disrupting centrosome-mediated MT assembly during mitosis.

Comparison of World Health Organization and Demographic and Health Surveys data to estimate sub-national deworming coverage in pre-school aged children.

BACKGROUND: The key metric for monitoring the progress of deworming programs in controlling soil-transmitted helminthiasis (STH) is national drug coverage reported to the World Health Organization (WHO). There is increased interest in utilizing geographically-disaggregated data to estimate sub-national deworming coverage and equity, as well as gender parity. The Demographic and Health Surveys (DHS) offer a potential source of sub-national data. This study aimed to compare deworming coverage routinely reported to WHO and estimated by DHS in pre-school aged children to inform global STH measurement and evaluation. METHODOLOGY: We compared sub-national deworming coverage in pre-school aged children reported to WHO and estimated by DHS aligned geospatially and temporally. We included data from Burundi (2016-2017), Myanmar (2015-2016), and the Philippines (2017) based on data availability. WHO provided data on the date and sub-national coverage per mass drug administration reported by Ministries of Health. DHS included maternally-reported deworming status within the past 6 months for each child surveyed. We estimated differences in sub-national deworming coverage using WHO and DHS data, and performed sensitivity analyses. PRINCIPAL FINDINGS: We compared data on pre-school aged children from 13 of 18 districts in Burundi (N = 6,835 in DHS), 11 of 15 districts in Myanmar (N = 1,462 in DHS) and 16 of 17 districts in the Philippines (N = 7,594 in DHS) following data exclusion. The national deworming coverages estimated by DHS in Burundi, Myanmar, and the Philippines were 75.5% (95% CI: 73.7%-77.7%), 47.0% (95% CI: 42.7%-51.3%), and 48.0% (95% CI: 46.0%-50.0%), respectively. The national deworming coverages reported by WHO in Burundi, Myanmar, and the Philippines were 80.1%, 93.6% and 75.7%, respectively. The mean absolute differences in district-level coverage reported to WHO and estimated by DHS in Burundi, Myanmar, and the Philippines were 9.5%, 41.5%, and 24.6%, respectively. Across countries, coverage reported to WHO was frequently higher than DHS estimates (32 of 40 districts). National deworming coverage from DHS estimates were similar by gender within countries. CONCLUSIONS AND SIGNIFICANCE: Agreement of deworming coverage reported to WHO and estimated by DHS data was heterogeneous across countries, varying from broadly compatible in Burundi to largely discrepant in Myanmar. DHS data could complement deworming data reported to WHO to improve data monitoring practices and serve as an independent sub-national source of coverage data.

The global progress of soil-transmitted helminthiases control in 2020 and World Health Organization targets for 2030.

Soil-transmitted helminth (STH) infections are the most widespread of the neglected tropical diseases, primarily affecting marginalized populations in low- and middle-income countries. More than one billion people are currently infected with STHs. For the control of these infections, the World Health Organization (WHO) recommends an integrated approach, which includes access to appropriate sanitation, hygiene education, and preventive chemotherapy (i.e., large-scale, periodic distribution of anthelmintic drugs). Since 2010, WHO has coordinated two large donations of benzimidazoles to endemic countries. Thus far, more than 3.3 billion benzimidazole tablets have been distributed in schools for the control of STH infections, resulting in an important reduction in STH-attributable morbidity in children, while additional tablets have been distributed for the control of lymphatic filariasis. This paper (i) summarizes the progress of global STH control between 2008 to 2018 (based on over 690 reports submitted by endemic countries to WHO); (ii) provides regional and country details on preventive chemotherapy coverage; and (iii) indicates the targets identified by WHO for the next decade and the tools that should be developed to attain these targets. The main message is that STH-attributable morbidity can be averted with evidence-informed program planning, implementation, and monitoring. Caution will still need to be exercised in stopping control programs to avoid any rebound of prevalence and loss of accrued morbidity gains. Over the next decade, with increased country leadership and multi-sector engagement, the goal of eliminating STH infections as a public health problem can be achieved.

Topoisomerase II and histone deacetylase inhibitors delay the G2/M transition by triggering the p38 MAPK checkpoint pathway.

When early prophase PtK(1) or Indian muntjac cells are exposed to topoisomerase II (topo II) inhibitors that induce little if any DNA damage, they are delayed from entering mitosis. We show that this delay is overridden by inhibiting the p38, but not the ATM, kinase. Treating early prophase cells with hyperosmotic medium or a histone deacetylase inhibitor similarly delays entry into mitosis, and this delay can also be prevented by inhibiting p38. Together, these results reveal that agents or stresses that induce global changes in chromatin topology during G2 delay entry into mitosis, independent of the ATM-mediated DNA damage checkpoint, by activating the p38 MAPK checkpoint. The presence of this pathway obviates the necessity of postulating the existence of multiple "chromatin modification" checkpoints during G2. Lastly, cells that enter mitosis in the presence of topo II inhibitors form metaphase spindles that are delayed in entering anaphase via the spindle assembly, and not the p38, checkpoint.

Extracellular signal-regulated kinase 1/2 activity is not required in mammalian cells during late G2 for timely entry into or exit from mitosis.

Extracellular signal-regulated kinase (ERK)1/2 activity is reported to be required in mammalian cells for timely entry into and exit from mitosis (i.e., the G2-mitosis [G2/M] and metaphase-anaphase [M/A] transitions). However, it is unclear whether this involvement reflects a direct requirement for ERK1/2 activity during these transitions or for activating gene transcription programs at earlier stages of the cell cycle. To examine these possibilities, we followed live cells in which ERK1/2 activity was inhibited through late G2 and mitosis. We find that acute inhibition of ERK1/2 during late G2 and through mitosis does not affect the timing of the G2/M or M/A transitions in normal or transformed human cells, nor does it impede spindle assembly, inactivate the p38 stress-activated checkpoint during late G2 or the spindle assembly checkpoint during mitosis. Using CENP-F as a marker for progress through G2, we also show that sustained inhibition of ERK1/2 transiently delays the cell cycle in early/mid-G2 via a p53-dependent mechanism. Together, our data reveal that ERK1/2 activity is required in early G2 for a timely entry into mitosis but that it does not directly regulate cell cycle progression from late G2 through mitosis in normal or transformed mammalian cells.

Sustained preventive chemotherapy for soil-transmitted helminthiases leads to reduction in prevalence and anthelminthic tablets required.

BACKGROUND: The goal of soil-transmitted helminthiases (STH) control programmes is to eliminate STH-associated morbidity in the target population by reducing the prevalence of moderate- and heavy-intensity infections and the overall STH infection prevalence mainly through preventive chemotherapy (PC) with either albendazole or mebendazole. Endemic countries should measure the success of their control programmes through regular epidemiological assessments. We evaluated changes in STH prevalence in countries that conducted effective PC coverage for STH to guide changes in the frequency of PC rounds and the number of tablets needed. METHODS: We selected countries from World Health Organization (WHO)'s Preventive Chemotherapy and Transmission control (PCT) databank that conducted ≥5 years of PC with effective coverage for school-age children (SAC) and extracted STH baseline and impact assessment data using the WHO Epidemiological Data Reporting Form, Ministry of Health reports and/or peer-reviewed publications. We used pooled and weighted means to plot the prevalence of infection with any STH and with each STH species at baseline and after ≥5 years of PC with effective coverage. Finally, using the WHO STH decision tree, we estimated the reduction in the number of tablets needed. RESULTS: Fifteen countries in four WHO regions conducted annual or semi-annual rounds of PC for STH for 5 years or more and collected data before and after interventions. At baseline, the pooled prevalence was 48.9% (33.1-64.7%) for any STH, 23.2% (13.7-32.7%) for Ascaris lumbricoides, 21.01% (9.7-32.3%) for Trichuris trichiura and 18.2% (10.9-25.5%) for hookworm infections, while after ≥5 years of PC for STH, the prevalence was 14.3% (7.3-21.3%) for any STH, 6.9% (1.3-12.5%) for A. lumbricoides, 5.3% (1.06-9.6%) for T. trichiura and 8.1% (4.0-12.2%) for hookworm infections. CONCLUSIONS: Countries endemic for STH have made tremendous progress in reducing STH-associated morbidity, but very few countries have data to demonstrate that progress. In this study, the data show that nine countries should adapt their PC strategies and the frequency of PC rounds to yield a 36% reduction in drug needs. The study also highlights the importance of impact assessment surveys to adapt control strategies according to STH prevalence.

Provision of deworming intervention to pregnant women by antenatal services in countries endemic for soil-transmitted helminthiasis.

BACKGROUND: The World Health Organization has recently reemphasized the importance of providing preventive chemotherapy to women of reproductive age in countries endemic for soil-transmitted helminthiasis as they are at heightened risk of associated morbidity. The Demographic and Health Surveys (DHS) Program is responsible for collecting and disseminating accurate, nationally representative data on health and population in developing countries. Our study aims to estimate the number of pregnant women at risk of soil-transmitted helminthiasis that self-reported deworming by antenatal services in endemic countries that conducted Demographic and Health Surveys. METHODOLOGY/PRINCIPAL FINDINGS: The number of pregnant women living in endemic countries was extrapolated from the United Nations World Population Prospects 2015. National deworming coverage among pregnant women were extracted from Demographic and Health Surveys and applied to total numbers of pregnant women in the country. Sub-national DHS with data on self-reported deworming were available from 49 of the 102 endemic countries. In some regions more than 73% of STH endemic countries had a DHS. The DHS report an average deworming coverage of 23% (CI 19-28), ranging from 2% (CI 1-3) to 35% (CI 29-40) in the different regions, meaning more than 16 million pregnant women were dewormed in countries surveyed by DHS. The deworming rates amongst the 43 million pregnant women in STH endemic countries not surveyed by DHS remains unknown. CONCLUSIONS/SIGNIFICANCE: These estimates will serve to establish baseline numbers of deworming coverage among pregnant women, monitor progress, and urge endemic countries to continue working toward reducing the burden of soil-transmitted helminthiasis. The DHS program should be extended to STH-endemic countries currently not covering the topic of deworming during pregnancy.

Estimation of the number of women of reproductive age in need of preventive chemotherapy for soil-transmitted helminth infections.

BACKGROUND: Soil-transmitted helminth infections are among the most common infections in developing countries. Globally, as many as 2 billion people are considered to be at risk for soil-transmitted-helminth (STH) infections. Preschool children (PSAC), school-age children (SAC) and women of reproductive age (WRA) are at high risk of STH-attributable morbidity and preventive chemotherapy (PC) for STH is recommended by the World health Organization (WHO). METHODOLOGY/PRINCIPAL FINDINGS: Over the last five years, PC coverage in PSAC and SAC has gradually increased, while coverage in WRA has lagged. Estimating the numbers of WRA in each endemic country would inform scale-up in this group. A two-step process was used: 1) total numbers of girls and women between 15 and 49 years of age were obtained from the United Nations World Population Prospects 2015 database; and 2) the proportion in need of PC was obtained primarily from extrapolation from the WHO PC Databank. WRA were divided into four sub-groups reflecting different reproductive life stages, each having a potentially different interface with the health care system and, consequently, presenting different opportunities for intervention strategies. Worldwide, we estimated that 688 million WRA in 102 countries were in need of PC for STH in 2015. The South-East Asia (49%) and Africa regions (26%) had the highest numbers. Adolescent girls accounted for 16%, while pregnant and lactating women each represented 10%. Over 25 million pregnant women alone were estimated living in areas where the prevalence of hookworm and T. trichiura infection was ≥ 20%. Approximately 20% of at-risk WRA had received deworming with albendazole through the Global Programme to Eliminate Filariasis. CONCLUSIONS/SIGNIFICANCE: To close current gaps in coverage, numbers of WRA in need of PC for STH are essential for operational strategies to control STH infection.

Monitoring equity in universal health coverage with essential services for neglected tropical diseases: an analysis of data reported for five diseases in 123 countries over 9 years.

BACKGROUND: A service coverage index has recently been proposed to monitor progress towards universal health coverage (UHC), and baseline results for 2015 are available. However, evidence on equity in that progress is scarce. The service coverage index did not consider services for neglected tropical diseases (NTDs), a group of preventable diseases defined by WHO member states on the basis of the disproportionate burden they place on their poorest, remotest, and otherwise most marginalised communities. Because of the much-needed equity lens that it could provide, NTD service coverage should not be neglected in efforts to monitor UHC progress. METHODS: We developed an index focused on coverage of services for NTDs, comparable in methods to the UHC service coverage index. On the basis of data availability, we focused on preventive chemotherapy, which was recently included in the highest-priority package of essential UHC interventions. We used data reported to WHO since 2008 for the five NTDs amenable to preventive chemotherapy (lymphatic filariasis, onchocerciasis, schistosomiasis, soil-transmitted helminthiases, and trachoma) to develop an NTD service coverage index based on the geometric mean of coverage rates for individual NTD services with regularly reported data. We then compared this NTD service coverage index with the UHC service coverage index. A high UHC index value and a low NTD index value suggest that a country might not be adequately prioritising interventions for the poor. We measured Spearman rank-order correlation (ρ) of the NTD service coverage index with income inequality, as measured by the Gini coefficient (range of 0-1), where values of the Gini coefficient close to 1 indicate higher income inequality, and a negative correlation was evidence of socioeconomic barriers to health service coverage for people who are least well off. FINDINGS: At least 123 countries can monitor NTD service coverage by use of a simple index. The median national NTD index was 32 in 2016, an increase from 3 in 2012, and from 0 in 2008. In 2015, the NTD index was lower than the UHC index in 81 of the 113 countries for which both NTD and UHC indices are available, by up to 80 points. The NTD index was negatively but weakly correlated with income inequality; this correlation was strongest in the African Region (ρ=-0·46 in 2008, ρ=-0·32 in 2015), suggesting that high-income inequality, although associated with low coverage of services targeting the poor, does not preclude the extension of that coverage. INTERPRETATION: The NTD index can be used to measure equity in progress towards UHC. A broader NTD index including services for other NTDs could be developed at regional and country levels. Comparing the NTD and UHC service coverage indices reveals that some countries that are performing well by the measure of the UHC service coverage index still have work to do in prioritising services for their poorest and otherwise most marginalised communities. Our results offer hope that socioeconomic barriers to health service coverage can be overcome. FUNDING: None.

Cell cycle: stressed out of mitosis.

Cells in early stages of chromosome condensation are very vulnerable, and many stresses that do not damage DNA induce a transient return to late G2 phase. Such stresses include the drug-induced disassembly of microtubules, which triggers an ATM-independent G2 checkpoint pathway involving a novel ubiquitin ligase.

DNA damage during mitosis in human cells delays the metaphase/anaphase transition via the spindle-assembly checkpoint.

BACKGROUND: DNA damage during mitosis triggers an ATM kinase-mediated cell cycle checkpoint pathway in yeast and fly embryos that delays progression through division. Recent data suggest that this is also true for mammals. Here we used laser microsurgery and inhibitors of topoisomerase IIalpha to break DNA in various mammalian cells after they became committed to mitosis. We then followed the fate of these cells and emphasized the timing of mitotic progression, spindle structure, and chromosome behavior. RESULTS: We find that DNA breaks generated during late prophase do not impede entry into prometaphase. If the damage is minor, cells complete mitosis on time. However, more significant damage substantially delays exit from mitosis in many cell types. In human (HeLa, CFPAC-1, and hTERT-RPE) cells, this delay occurs during metaphase, after the formation of a bipolar spindle and the destruction of cyclin A, and it is not dependent on a functional p53 pathway. Pretreating cells with ATM kinase inhibitors does not abrogate the metaphase delay due to chromosome damage. Immunofluorescence studies reveal that cells blocked in metaphase by chromosome damage contain one or more Mad2-positive kinetochores, and the block is rapidly overridden when the cells are microinjected with a dominant-negative construct of Mad2 (Mad2deltaC). CONCLUSIONS: We conclude that the delay in mitosis induced by DNA damage is not due to an ATM-mediated DNA damage checkpoint pathway. Rather, the damage leads to defects in kinetochore attachment and function that, in turn, maintain the intrinsic Mad-2-based spindle assembly checkpoint.

A practical approach for scaling up the alternative strategy for the elimination of lymphatic filariasis in Loa loa endemic countries - developing an action plan.

BACKGROUND: Lymphatic filariasis (LF) is a vector-borne parasitic disease that is being targeted for elimination through mass drug administration (MDA). The co-distribution of Loa loa in Central Africa poses a significant barrier to the expansion of the MDA due to risk of severe adverse events (SAEs) associated with the drug ivermectin that is routinely used. National LF programmes are yet to significantly scale up in co-endemic areas and need a practical approach to make preliminary decisions based on the mapping status and potential treatment strategies. METHODS: We reviewed relevant data available to WHO and in the literature for LF-L. loa endemic countries to develop a simple method to support the scale-up of MDA to eliminate LF. RESULTS: A basic model for national LF programmes to work from at the administrative or implementation unit (IU) level has been developed for LF - L. loa co-endemic countries. The model includes five practical steps, which comprise the development of a national filarial database and a simple classification system to help determine the mapping status and most appropriate treatment strategy. Steps are colour-coded and linked to a general decision tree, which is also presented. CONCLUSIONS: This IU-level model is simple to follow and will help LF elimination programmes develop an action plan and scale up the implementation of alternative treatment strategies in L. loa co-endemic areas. The model could be further developed to incorporate the additional complexity of IUs where an intervention is required to eliminate onchocerciasis, particularly in hypo-endemic areas where ivermectin has not been used.

The Impact of Lymphatic Filariasis Mass Drug Administration Scaling Down on Soil-Transmitted Helminth Control in School-Age Children. Present Situation and Expected Impact from 2016 to 2020.

Lymphatic filariasis (LF) and soil-transmitted-helminths (STH) are co-endemic in 58 countries which are mostly in Africa and Asia. Worldwide, 486 million school-age children are considered at risk of both diseases. In 2000, the World Health Organization (WHO) established the global programme to eliminate LF by 2020. Since then, the LF elimination programme has distributed ivermectin or diethylcarbamazine citrate (DEC) in combination with albendazole, thereby also treating STH. Consequently, many school-age children have been treated for STH through the LF programme. As treatment targets towards the 2020 LF elimination goal are achieved, many countries are implementing the transmission assessment survey (TAS) and, if the LF prevalence is estimated to be less than 1%, scaling down mass drug administration (MDA). We analysed the 2014 data on preventive chemotherapy (PC) reported from LF STH co-endemic countries and projected the year and location of TAS expected to be conducted between 2016 and 2020 to assess the impact of this scaling down on STH PC. Eighty percent of all co-endemic countries that have already stopped LF MDA nationally were able to establish STH PC through schools. It is estimated that 14% of the total number of children presently covered by the LF programme is at risk of not continuing to receive PC for STH. In order to achieve and maintain the WHO 2020 goal for STH control, there is an urgent need to establish and reinforce school-based deworming programmes in countries scaling-down national LF elimination programmes.