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PubMed2005

Swallowing dysfunction in patients with unilateral vocal fold paralysis: aetiology and outcomes.

Although unilateral vocal fold palsy (UVFP) is a common problem, data relating to swallowing dysfunction are sparse. We reviewed the clinical findings (method of presentation, underlying diagnosis and position of the vocal folds) of 30 patients and conducted a follow-up telephone survey. Outcome measures used were direct visualization of fold function, position and compensation. In addition, standardized speech and language assessments for swallowing dysfunction and dysphonia were noted and compared to presentation. Our study indicates that 56 per cent of patients with UVFP have associated dysphagia. Outcome with speech therapy is significant, with 73 per cent showing improvement. These data indicate a significant link between UVFP and swallowing dysfunction. There is a marked therapeutic benefit from voice therapy. Further work is required to evaluate the long-term outcomes and establish the mechanism of swallowing dysfunction in these patients.

Adult↗

PubMed2006

Consumption of 'extra' foods (energy-dense, nutrient-poor) among children aged 16-24 months from western Sydney, Australia.

OBJECTIVE: This study evaluates the contribution of energy-dense, nutrient-poor 'extra' foods to the diets of 16-24-month-old children from western Sydney, Australia. DESIGN: An analysis of cross-sectional data collected on participants in the Childhood Asthma Prevention Study (CAPS), a randomised trial investigating the primary prevention of asthma from birth to 5 years. We collected 3-day weighed food records, calculated nutrient intakes, classified recorded foods into major food groups, and further classified foods as either 'core' or 'extras' according to the Australian Guide to Healthy Eating. SETTING: Pregnant women, whose unborn child was at risk of developing asthma because of a family history, were recruited from all six hospitals in western Sydney, Australia. Data for this study were collected in clinic visits and at participants' homes at the 18-month assessment. PARTICIPANTS: Four hundred and twenty-nine children participating in the CAPS study; 80% of the total cohort. RESULTS: The mean consumption of 'extra' foods was approximately 150 g day(-1) and contributed 25-30% of the total energy, fat, carbohydrate and sodium to the diets of the study children. 'Extra' foods also contributed around 20% of fibre, 10% of protein and zinc, and about 5% of calcium. Children in the highest quintile of 'extra' foods intake had a slightly higher but not significantly different intake of energy from those in the lowest quintile. However, significant differences were evident for the percentage of energy provided by carbohydrate and sugars (higher) and protein and saturated fat (lower). The intake of most micronutrients was also significantly lower among children in the highest quintile of consumption. The intake of 'extra' foods was inversely associated with the intake of core foods. CONCLUSIONS: The high percentage of energy contributed by 'extra' foods and their negative association with nutrient density emphasise the need for dietary guidance for parents of children aged 1-2 years. These preliminary data on commonly consumed 'extra' foods and portion sizes may inform age-specific dietary assessment methods.

Australia↗

PubMed2004

Serum peptide profiling by magnetic particle-assisted, automated sample processing and MALDI-TOF mass spectrometry.

Human serum contains a complex array of proteolytically derived peptides (serum peptidome) that may provide a correlate of biological events occurring in the entire organism; for instance, as a diagnostic for solid tumors (Petricoin, E. F.; Ardekani, A. M.; Hitt, B. A.; Levine, P. J.; Fusaro, V. A.; Steinberg, S. M.; Mills, G. B.; Simone, C.; Fishman, D. A.; Kohn, E. C.; Liotta, L. Lancet 2002, 359, 572-577). Here, we describe a novel, automated technology platform for the simultaneous measurement of serum peptides that is simple, scalable, and generates highly reproducible patterns. Peptides are captured and concentrated using reversed-phase (RP) batch processing in a magnetic particle-based format, automated on a liquid handling robot, and followed by a MALDI TOF mass spectrometric readout. The protocol is based on a detailed investigation of serum handling, RP ligand and eluant selection, small-volume robotics design, an optimized spectral acquisition program, and consistent peak extraction plus binning across a study set. The improved sensitivity and resolution allowed detection of 400 polypeptides (0.8-15-kDa range) in a single droplet (approximately 50 microL) of serum, and almost 2000 unique peptides in larger sample sets, which can then be analyzed using common microarray data analysis software. A pilot study indicated that sera from brain tumor patients can be distinguished from controls based on a pattern of 274 peptide masses. This, in turn, served to create a learning algorithm that correctly predicted 96.4% of the samples as either normal or diseased.

Algorithms↗

PubMed1992

Relationships between secondary structure fractions for globular proteins. Neural network analyses of crystallographic data sets.

The relationship between the fractions of protein secondary structural components as determined from X-ray crystallographic data by the procedures of Kabsch and Sander (KS) and of Levitt and Greer (LG) is analyzed by neural network analysis of these two tabulations of literature data. A linear relationship between the KS and LG reductions of X-ray data to secondary structure descriptors is demonstrated by a regression analysis of the relationships between these sets of structural parameters. Back-propagation neural network analysis was then used to derive equations for determination of the most probable fractions of beta-sheet, bend, turn, and "other" conformations given the fraction of alpha-helix in a globular protein. The deviation of the X-ray values for beta-sheet from that determined with these equations was shown to have a variance that exponentially decreased with increasing fraction of alpha-helix. A second neural network analysis showed that knowledge of both the alpha-helical and beta-sheet fractions in a protein significantly reduces the uncertainty in prediction of the other components of the secondary structure. These analyses provide insight into the nature of the data sets derived from crystal structures. Since these complications of crystal structure data are commonly used as reference information for quantitative evaluation of spectra (for example, FTIR, Raman, and electronic or vibrational circular dichroism) in terms of secondary structure, such internal correlations in the reference sets may have significant effects on the stability of spectroscopic analyses derived from them.

Mathematics↗

PubMed1996

Multiple-Edge XAS Studies of Synthetic Iron-Copper Bridged Molecular Assemblies Relevant to Cytochrome c Oxidase. Structure Determination Using Multiple-Scattering Analysis with Statistical Evaluation of Errors.

An X-ray absorption spectroscopy study has been carried out at the Fe and Cu K-edges for two bridged molecular assemblies, both of which contain an Fe-X-Cu (X = O(2)(-), OH(-)) bridge unit, some of whose features are relevant to the binuclear site of cytochrome c oxidase. The two complexes [(OEP)Fe-O-Cu(Me(6)tren)](1+) and [(OEP)Fe-(OH)-Cu(Me(5)tren)(OClO(3))](1+) have similar structural fragments around the metal centers except that they differ significantly in the bridge structure (the former contains a linear oxo bridge while the latter has a bent hydroxo bridge). We report a comparative study of these complexes using multiple-scattering (MS) EXAFS analysis and the program package GNXAS. It is found that there is a dramatic increase in the amplitude of the Fe-X-Cu MS pathway as the bridge unit approaches linearity. Full EXAFS MS analysis enables accurate quantitation of bridge metrical details and geometry for both complexes. These studies were done with an expanded version of GNXAS, which allows for simultaneous multiple-edge fitting. Such multiple-edge analysis (using both Fe and Cu edge data) allows common pathways (in this case involving the Fe-X-Cu bridge) to be constrained to be the same, thus improving the observation/variable ratio and enhancing sensitivity for determination of the bridge structure. The accuracy of the structural determination for the bridge units is evaluated by a statistical analysis methodology in which correlations among fitting parameters are identified and contour plots are used to determine random error. The overall error in the EXAFS structural determination is found by establishing the variance with the crystallographically determined values: for the EXAFS-determined parameters at distances below 4 Å, distances and angles deviated on average from crystallographic values by 0.014 Å and 1.5 degrees, respectively. It is also established that structural features in the Fe absorption preedge are diagnostic of oxo vs hydroxo ligation. The relevance of this study to the structural definition of binuclear bridged sites in cytochrome c oxidase and other metalloenzymes is considered.

Journal Article↗

PubMed2002

Antimicrobial furostanol saponins from the seeds of Capsicum annuum L. var. acuminatum.

Three new furostanol saponins named capsicoside E (1), capsicoside F (2), and capsicoside G (5) were obtained from the seeds of Capsicum annuum L. var. acuminatum along with known oligoglycosides (3, 4, and 6-10). On the basis of chemical and spectroscopic analyses, the structures of these new furostanol oligoglycosides were elucidated as 26-O-beta-D-glucopyranosyl-22-O-methyl-5alpha-furost-25(27)-en-2alpha,3beta,22xi,26-tetraol-3-O-beta-D-glucopyranosyl(1-->3)-beta-D-glucopyranosyl(1-->2)-[beta-D-glucopyranosyl(1-->3)]-beta-D-glucopyranosyl(1-->4)-beta-D-galactopyranoside (1), 26-O-beta-D-glucopyranosyl-(25R)-5alpha-furost-20(22)-en-2alpha,3beta,26-triol-3-O-beta-D-glucopyranosyl (1-->3)-beta-D-glucopyranosyl(1-->2)-[beta-D-glucopyranosyl(1-->3)]-beta-D-glucopyranosyl(1-->4)-beta-D-galactopyranoside (2), and 26-O-beta-D-gluco-pyranosyl-(25R)-5alpha-furosta-3beta,22xi,26-triol-3-O-beta-D-glucopyranosyl(1-->3)-beta-D-glucopyranosyl(1-->2)-[beta-D-glucopyranosyl(1-->3)]-beta-D-glucopyranosyl(1-->4)-beta-D-galactopyranoside (5). The isolated saponins showed higher antimicrobial activity against yeasts than against common fungi. Data indicated that the antiyeast activity was related to the combination of the oligosaccharide chain (S1, S2, or S3) with an O-methyl group at R(3) and the presence of a hydroxyl group at the C-2 position.

Anti-Bacterial Agents↗

PubMed1998

Failure inference from a marker process based on a bivariate Wiener model.

Many models have been proposed that relate failure times and stochastic time-varying covariates. In some of these models, failure occurs when a particular observable marker crosses a threshold level. We are interested in the more difficult, and often more realistic, situation where failure is not related deterministically to an observable marker. In this case, joint models for marker evolution and failure tend to lead to complicated calculations for characteristics such as the marginal distribution of failure time or the joint distribution of failure time and marker value at failure. This paper presents a model based on a bivariate Wiener process in which one component represents the marker and the second, which is latent (unobservable), determines the failure time. In particular, failure occurs when the latent component crosses a threshold level. The model yields reasonably simple expressions for the characteristics mentioned above and is easy to fit to commonly occurring data that involve the marker value at the censoring time for surviving cases and the marker value and failure time for failing cases. Parametric and predictive inference are discussed, as well as model checking. An extension of the model permits the construction of a composite marker from several candidate markers that may be available. The methodology is demonstrated by a simulated example and a case application.

Biometry↗

PubMed2000

Going back to the roots: effective utilisation of HLA typing information for bone marrow registries requires full knowledge of the DNA sequences of the oligonucleotide reagents used in the testing.

Information obtained by DNA-based HLA typing assays is more detailed and of higher quality than that obtained by conventional serological techniques. Nevertheless, it is common for data acquired in this way to be presented in the more familiar serological format. In many cases this representation can lead to significant loss of information, which may only become apparent at a later time, with the discovery of novel allele sequences. DNA-based typing methods, such as sequence-specific oligonucleotide probing (SSOP) or sequence-specific priming (SSP) generate fragmentary sequence data which is information rich. An alternative to assigning allele names to these fragments is to simply store the sequence data itself without interpretation. Bone marrow donor repositories can then be searched directly with sequence information, which though complex is more complete, rather than searching by derivative allele names.

Base Sequence↗

PubMed2006

Modeling heterogeneity in social interaction processes using multilevel survival analysis.

More than 15 years ago, survival or hazard regression analyses were introduced to psychology (W. Gardner & W. A. Griffin, 1989; W. A. Griffin & W. Gardner, 1989) as powerful methodological tools for studying real time social interaction processes among dyads. Almost no additional published applications have appeared, although such data are commonly collected and the applicable questions are central to many important theoretical perspectives. To revisit the basic methods, the authors use an example from emotion regulation theory in which the level of child antisocial behavior is hypothesized to be positively associated with the hazard rate of angry emotions and negatively associated with sad, fearful emotions in the face of parental negative behavior (scolding). The authors discuss the limitations of traditional approaches to the analysis of social interaction and demonstrate improvements in the ability to model individual differences now available in existing software.

Antisocial Personality Disorder↗

PubMed2005

A new score for predicting neonatal very low birth weight mortality risk in the NEOCOSUR South American Network.

OBJECTIVE: To develop and validate a model for very low birth weight (VLBW) neonatal mortality prediction, based on commonly available data at birth, in 16 neonatal intensive care units (NICUs) from five South American countries. STUDY DESIGN: Prospectively collected biodemographic data from the Neonatal del Cono Sur (NEOCOSUR) Network between October 2000 and May 2003 in infants with birth weight 500 to 1500 g were employed. A testing sample and crossvalidation techniques were used to validate a statistical model for risk of in-hospital mortality. The new risk score was compared with two existing scores by using area under the receiver operating characteristic curve (AUC). RESULTS: The new NEOCOSUR score was highly predictive for in-hospital mortality (AUC=0.85) and performed better than the Clinical Risk Index for Babies (CRIB) and the NICHD risk models when used in the NEOCOSUR Network. The new score is also well calibrated - it had good predictive capability for in-hospital mortality at all levels of risk (HL test=11.9, p=0.85). The new score also performed well when used to predict in hospital neurological and respiratory complications. CONCLUSIONS: A new and relatively simple VLBW mortality risk score had a good prediction performance in a South American network population. This is an important tool for comparison purposes among NICUs. This score may prove to be a better model for application in developing countries.

Female↗

PubMed2003

Antecedent use of fluoroquinolones is associated with resistance to moxifloxacin in Clostridium difficile.

OBJECTIVE: Moxifloxacin is characterized by high activity against Gram-positive cocci and some Gram-positive and -negative anaerobes, including Clostridium difficile. This study investigates the role of prior quinolone use in relation to patterns of susceptibility of C. difficile to moxifloxacin. METHODS: Sixty-three clinical isolates of C. difficile were investigated for toxigenicity, susceptibility to moxifloxacin, and mutations in the DNA gyrase gene. The medical histories for 50 of these patients were available and used to identify previous fluoroquinolone use. RESULTS: Thirty-three (52.4%) strains showed resistance to moxifloxacin (MICs > or = 16 mg/L). All moxifloxacin-resistant strains harbored a mutation at amino acid codon Ser-83 of gyrA. Forty-five isolates (71.4%) were toxigenic; all moxifloxacin-resistant strains were in this group. Resistance to moxifloxacin was associated with prior use of fluoroquinolones (P-value 0.009, chi-square). CONCLUSIONS: Although the use of moxifloxacin to treat C. difficile-associated diarrhea is not likely to be common, these data show a relationship between antecedent fluoroquinolone use and resistance to moxifloxacin in C. difficile isolates, and raise questions regarding selection pressure for resistance placed on colonizing bacteria exposed to fluoroquinolones. Mutations in gyrA are involved in moxifloxacin resistance.

Anti-Infective Agents↗

PubMed1999

Selective blocking effects of tropisetron and atropine on recombinant glycine receptors.

Some serotonin 5-HT3 receptor ligands of tropeine structure have been recently shown to modulate ionophore function and binding of glycine receptors. This led us to study the effects of the tropeines tropisetron and atropine on recombinant human glycine receptors transiently expressed in Xenopus oocytes by using whole-cell voltage-clamp electrophysiology. Glycine currents were inhibited by atropine in an apparently competitive manner and with considerable selectivity of the tropeines for alpha2 versus alpha1 subunits. Coexpression of beta with alpha subunits and replacement of the N-terminal region of the alpha1 subunits by the corresponding beta segment resulted in similar increases in the inhibitory potencies. Our data suggest common sites of the tropeines for inhibition on the N-terminal region of glycine receptors. The point mutations R271K and R271L of the alpha1 subunit decreased, whereas a T112A substitution increased, the inhibition constants (Ki) of the tropeines. These changes in the Ki values of the tropeines were associated with opposite changes in the EC50 of glycine. Selectivities for the tropeines versus glycine (EC50/Ki) varied within three orders of magnitude. These results, when expressed in terms of free energy changes, can be interpreted according to a two-state receptor model.

Animals↗

PubMed2000

Health-related quality of life outcomes measures.

OBJECTIVE: To review critically the features of measures of generic health-related quality of life (HRQOL) for disability outcomes research. DATA SOURCES: A search of electronic databases, summary reviews, books, and government documents was performed. Comment and experiences from participants of a conference on outcomes research were also incorporated. STUDY SELECTION: English language literature from scientists from a broad range of disciplines and research settings, including medicine, nursing, social science, and public health, and health services research and practice. DATA EXTRACTION: A critical review of measures that have been or might be used to measure disability outcomes. DATA SYNTHESIS: Commonly used generic measures of HRQOL can be applied to disability outcomes research with some caveats. Three common tools are the Medical Outcomes Study Short-Form Health Survey (SF-36), Sickness Impact Profile (SIP), and Quality of Well-Being (QWB) scale. The SF-36 and SIP have been used with some success in research with people with disability. The QWB scale has been used less frequently. CONCLUSION: Most studies using generic HRQOL tools are of groups with specific impairments rather than heterogeneous groups of people with disability. None of the tools appears to measure HRQOL without some potential biases (eg, inappropriate wording) for people with disability, but more specific testing of these problems is needed. Also needed are studies to determine whether these tools can measure meaningful longitudinal changes.

Persons with Disabilities↗

PubMed1999

Dorsal fracture dislocations of the proximal interphalangeal joint: surgical complications and long-term results.

This retrospective study assessed the short-term complications and long-term subjective and objective results of operative treatment of acute unstable dorsal proximal interphalangeal joint dislocations treated by 2 methods: open reduction internal fixation and volar plate arthroplasty. Fifty-six patients were included in this study. Twenty-three (41%) were treated by volar plate arthroplasty and 33 (59%) were treated by open reduction internal fixation. Postoperative complications occurred in 10 patients (18%). The most frequent complication was redislocation, which occurred in 6 patients (volar plate arthroplasty, 3 patients; open reduction internal fixation, 3 patients) and necessitated salvage surgery in 4 of these 6 cases. In all 6 cases, the fracture of the base of the middle phalanx involved more than 50% of the articular surface. Twenty-four patients (43%) returned for long-term evaluation at an average follow-up period of 46 months (range, 13-125 months). Twenty of these 24 patients (83%) reported little or no pain despite a high incidence (96%) of posttraumatic degenerative changes. Eighteen (75%) reported no difficulty with work activities; 92% continued leisure activities with little or no modification. Proximal interphalangeal joint flexion contractures and extension lag at the distal interphalangeal joint were common. These data indicate that if reduction is maintained, patients may expect few functional deficits despite radiographic degenerative changes and loss of mobility.

Adult↗

PubMed2006

Listening to female sex workers in Vietnam: influences on safe-sex practices with clients and partners.

BACKGROUND: This qualitative study assessed HIV/AIDS knowledge and frequency of and influences on condom use with clients and regular, non-client partners among female sex workers (FSWs) in Khanh Hoa, a tourist-oriented province of central Vietnam where sex work is common. METHODS: Data were collected via semi-structured interviews with indirect (n = 16) and direct (n = 9) FSWs. RESULTS: Although the majority of respondents were well informed about HIV/AIDS transmission, about one-third had inaccurate beliefs about HIV-positive people as well as the mechanisms by which HIV is transmitted from mother to child. Condom use was inconsistent. More direct than indirect FSWs reported using condoms most of the time with clients but none used condoms all the time. With regular partners, most respondents reported that they never used condoms. Around one-third of women hid their sex work from their regular partners, who made the decision to use or not to use condoms. The most frequently reported reasons for not using condoms with clients were because clients offered a higher price, clients insisted on condom-free sex, and possession of condoms as evidence of sex worker status. For regular partners, the reasons were familiarity, condom use being dependent on partner's decision, and condom use as evidence of sex worker status. There was no apparent relationship between HIV knowledge, time in sex work, and safe sex practices. CONCLUSION: Recommendations are made to improve the rate of condom use among FSWs.

Adolescent↗

PubMed2001

UV irradiation augments lymphoid malignancies in mice with one functional copy of wild-type p53.

Epidemiological studies have suggested an association between exposure to solar UV radiation and the incidence of lymphoid malignancies, which has increased substantially worldwide during the last two decades. Findings from animal studies have raised the question of whether UV radiation might influence the development of lymphoid malignancies by means of its immunosuppressive effect. In this study, we examined the effect of UV irradiation on the development of lymphoid malignancies in mice with no or only one functional copy of p53. Mice that lack both copies of p53 spontaneously develop high frequency of lymphoid malignancies in the thymus and spleen. p53 heterozygous mice with only one copy of the wild-type allele also develop lymphoid malignancies, but with a much lower frequency and a long latent period. In our study using mice of the C57BL/6 background, only one of the unirradiated mice lacking one copy of p53 (p53(+/-)) spontaneously developed a lymphoid tumor (6%), whereas 88% of UV-irradiated p53(+/-) mice developed lymphoid tumors in the spleen or liver. None of the control or UV-irradiated p53 wild-type mice developed lymphoid tumors during the 60-week observation period. Both UV-irradiated and unirradiated mice lacking both copies of p53 (p53(-/-)) rapidly developed thymic lymphomas and/or lymphoid tumors in spleen or liver. All of the lymphoid tumors tested were of T cell type. The immune responses of the mice to contact sensitization were identical and were suppressed to the same extent by UV irradiation regardless of the genotype. These results indicate that differences in immune reactivity do not account for the different effects of UV radiation on lymphoid malignancies and, in addition, that p53 is not required for generation of T cell-mediated immunity. Interestingly, whereas p53 mutations or loss of heterozygosity did not account for the accelerated development of lymphoid tumors in UV-irradiated p53(+/-) mice, deletions in the p16(INK4a) gene were quite common. These data provide the experimental evidence that UV irradiation induces lymphoid neoplasms in genetically susceptible mice and support the hypothesis that extensive sunlight exposure contributes to the induction of lymphoma in humans.

Age Factors↗

PubMed1982

Presecretory and cytoplasmic invertase polypeptides encoded by distinct mRNAs derived from the same structural gene differ by a signal sequence.

Saccharomyces cerevisiae strain FH4C carries a single invertase structural gene, SUC2, but produces distinct invertase mRNAs and polypeptides for the secreted and cytoplasmic forms of the enzyme. The two major invertase cell-free translation products are polypeptides of 60,000 daltons (p60) and 62,000 daltons (p62) and correspond to the nonglycosylated cytoplasmic form of invertase and the precursor of glycosylated secreted invertase, respectively. This paper describes amino acid sequence and peptide map analyses of invertase polypeptides. The peptide maps demonstrate that p62, p60, and the in vivo secreted polypeptide have significant structural homology. Sequence analysis, however, revealed differences between p62 and p60 at their amino termini. p62 contains an amino-terminal signal sequence of 19 amino acid residues that is specifically cleaved during secretion in a cell-free system to generate the secreted 87,000-dalton invertase glycopeptide gp87. This signal sequence is not present in p60. p60 synthesis begins with a methionine which can be aligned with a methionine at residue 21 in p 62. During translation, the p60 initiator methionine is removed and the newly generated amino terminus is acetylated. Based on peptide map similarities, partial amino-terminal sequence data, and common genetic origin, it is suggested that p60 and p62 have identical amino acid sequences carboxy-terminal to the p60 initiator methionine (residue 21 of p62). The reciprocal correlations of signal sequence with secretion and absence of signal sequence with cytoplasmic localization provide proof of the signal hypothesis for secreted proteins. Two mechanisms are proposed for the derivation of p60 and p62 from a single structural gene: alternative promoter sites, and differential processing of a single primary transcript.

Amino Acid Sequence↗

PubMed2001

Patterns of spread in biological invasions dominated by long-distance jump dispersal: Insights from Argentine ants.

Invading organisms may spread through local movements (giving rise to a diffusion-like process) and by long-distance jumps, which are often human-mediated. The local spread of invading organisms has been fit with varying success to models that couple local population growth with diffusive spread, but to date no quantitative estimates exist for the relative importance of local dispersal relative to human-mediated long-distance jumps. Using a combination of literature review, museum records, and personal surveys, we reconstruct the invasion history of the Argentine ant (Linepithema humile), a widespread invasive species, at three spatial scales. Although the inherent dispersal abilities of Argentine ants are limited, in the last century, human-mediated dispersal has resulted in the establishment of this species on six continents and on many oceanic islands. Human-mediated jump dispersal has also been the primary mode of spread at a continental scale within the United States. The spread of the Argentine ant involves two discrete modes. Maximum distances spread by colonies undergoing budding reproduction averaged 150 m/year, whereas annual jump-dispersal distances averaged three orders of magnitude higher. Invasions that involve multiple dispersal processes, such as those documented here, are undoubtedly common. Detailed data on invasion dynamics are necessary to improve the predictive power of future modeling efforts.

Animals↗